Evidence Report/Technology Assessment Number 89

Transcription

1 Evidence Report/Technology Assessment Number 89 Effects of Omega-3 Fatty Acids on Lipids and Glycemic Control in Type II Diabetes and the Metabolic Syndrome and on Inflammatory Bowel Disease, Rheumatoid Arthritis, Renal Disease, Systemic Lupus Erythematosus, and Osteoporosis Prepared for: Agency for Healthcare Research and Quality U.S. Department of Health and Human Services 540 Gaither Road Rockville, MD Contract No Prepared by: Southern California/RAND Evidence-based Practice Center, Los Angeles, CA Program Directors Paul G. Shekelle, MD, PhD Sally C. Morton, PhD Project Director Catherine H. MacLean, MD, PhD Project Manager Rena Hasenfeld Garland, BA Statistician Wenli Tu, MS Programmer/Analyst Lara K. Jungvig, BA Scientific Reviewers Walter A. Mojica, MD, MPH James Pencharz, BSc (Kin) Jennifer Grossman, MD Puja Khanna, MD, MPH Editor Sydne J. Newberry, PhD Technical Advisors Ian Gralnek, MD, MSHS Alan Nissenson, MD Librarians Jessie McGowan, MLIS Nancy Santesso, RD, MLIS Staff Assistants Donna Mead, BA Shannon Rhodes, MFA Shana Traina, MA AHRQ Publication No. 04-E012-2 March 2004

2 This report may be used, in whole or in part, as the basis for development of clinical practice guidelines and other quality enhancement tools, or a basis for reimbursement and coverage policies. AHRQ or U.S. Department of Health and Human Services endorsement of such derivative products may not be stated or implied. AHRQ is the lead Federal agency charged with supporting research designed to improve the quality of health care, reduce its cost, address patient safety and medical errors, and broaden access to essential services. AHRQ sponsors and conducts research that provides evidence-based information on health care outcomes; quality; and cost, use, and access. The information helps health care decisionmakers patients and clinicians, health system leaders, and policymakers make more informed decisions and improve the quality of health care services.

3 This document is in the public domain and may be used and reprinted without permission except those copyrighted materials noted for which further reproduction is prohibited without the specific permission of copyright holders. Suggested Citation: MacLean CH, Mojica, WA, Morton SC, Pencharz J, Hasenfeld Garland R, Tu W, Newberry SJ, Jungvig LK, Grossman J, Khanna P, Rhodes S, Shekelle P. Effects of Omega-3 Fatty Acids on Lipids and Glycemic Control in Type II Diabetes and the Metabolic Syndrome and on Inflammatory Bowel Disease, Rheumatoid Arthritis, Renal Disease, Systemic Lupus Erythematosus, and Osteoporosis. Evidence Report/Technology Assessment. No. 89 (Prepared by Southern California/RAND Evidence-based Practice Center, under Contract No ). AHRQ Publication No. 04-E Rockville, MD: Agency for Healthcare Research and Quality. March ii

4 Preface The Agency for Healthcare Research and Quality (AHRQ), through its Evidence-based Practice Centers (EPCs), sponsors the development of evidence reports and technology assessments to assist public- and private-sector organizations in their efforts to improve the quality of health care in the United States. This report on Effects of Omega-3 Fatty Acids on Lipids and Glycemic Control in Type II Diabetes and the Metabolic Syndrome and on Inflammatory Bowel Disease, Rheumatoid Arthritis, Renal Disease, Systemic Lupus Erythematosus, and Osteoporosis was requested and funded by the Office of Dietary Supplements, National Institutes of Health, through the EPC Program at the Agency for Healthcare Research and Quality. The reports and assessments provide organizations with comprehensive, science-based information on common, costly medical conditions and new health care technologies. The EPCs systematically review the relevant scientific literature on topics assigned to them by AHRQ and conduct additional analyses when appropriate prior to developing their reports and assessments. To bring the broadest range of experts into the development of evidence reports and health technology assessments, AHRQ encourages the EPCs to form partnerships and enter into collaborations with other medical and research organizations. The EPCs work with these partner organizations to ensure that the evidence reports and technology assessments they produce will become building blocks for health care quality improvement projects throughout the Nation. The reports undergo peer review prior to their release. AHRQ expects that the EPC evidence reports and technology assessments will inform individual health plans, providers, and purchasers as well as the health care system as a whole by providing important information to help improve health care quality. We welcome written comments on this evidence report. They may be sent to: Director, Center for Outcomes and Evidence, Agency for Healthcare Research and Quality, 540 Gaither Road, Rockville, MD Carolyn M. Clancy, M.D. Director Agency for Healthcare Research and Quality Paul Coates, Ph.D. Director, Office of Dietary Supplements National Institutes of Health Jean Slutsky, P.A., M.S.P.H. Acting Director, Center for Outcomes and Evidence Agency for Healthcare Research and Quality The authors of this report are responsible for its content. Statements in the report should not be construed as endorsement by the Agency for Healthcare Research and Quality or the U.S. Department of Health and Human Services of a particular drug, device, test, treatment, or other clinical service. iii

5 Acknowledgments We thank Herbert D. Woolf, PhD, of BASF Corporation for providing us with unpublished data on omega-3 fatty acids. We thank Antonio LaCava, MD, PhD for providing translation of Italian studies, Takahiro Higashi, MD for providing translation of Japanese studies, Markus Rihl, MD for providing translation of German studies, and Anna Maria Björnsdotter, BA, for providing translation of Swedish studies. Chapter 1 was written in collaboration with the Tufts-New England Medical Center Evidence-based Practice Center. iv

6 Structured Abstract Context: Clinical trials report differing effects of omega-3 fatty acids on lipids and glycemic control in type II diabetes and the metabolic syndrome and on inflammatory bowel disease (IBD), rheumatic arthritis, renal disease, systemic lupus erythemosus (SLE), and osteoporosis. Objectives: To assess the effect of omega-3 fatty acids on 1) total cholesterol, LDL cholesterol, HDL cholesterol, triglycerides, and insulin resistance in type-ii diabetes and the metabolic syndrome, 2) clinical score, sigmoidoscopic score, histologic score and requirement for immunosuppressive therapy in IBD, 3) pain, swollen and tender joint counts, acute phase reactants, patient global assessment, and requirement for anti-inflammatory or immunosuppressive therapy in rheumatoid arthritis, 4) renal function, progression to end-stage renal disease, hemodialysis graft patency, mortality, and requirement for immunosuppressive therapy in renal disease, 5) disease activity, damage, patient s perception of disease activity, and requirement for immunosuppressive therapy in SLE, and 6) bone mineral density and fracture rates. Data Sources: We searched on-line databases to identify potentially relevant studies and contacted industry experts for unpublished data. Study Selection: We screened 4,212 titles, reviewed 1,097 articles, and included 83 articles. We restricted to randomized controlled trials (RCTs), but included case-control and cohort studies for bone/fracture. We had no language restrictions. Data Extraction: We abstracted data on study design, study population, and outcomes; source, amount, and duration of omega-3 fatty acid consumption; and randomization, dropouts, blinding, and allocation for RCTs. Data Synthesis: We performed meta-analyses for diabetes, rheumatoid arthritis, and IBD; and qualitative analyses for the other conditions. For diabetes, omega-3 fatty acids had a favorable effect on triglyceride levels but no significant effect on total cholesterol, HDL cholesterol, LDL cholesterol, fasting blood sugar, or glycosylated hemoglobin. There was no effect on plasma insulin or insulin resistance in type II diabetics or the metabolic syndrome. For IBD, omega-3 fatty acids had variable effects on clinical score, sigmoidoscopic score, histologic score, induced remission, and relapse, and no effect on the relative risk of relapse in ulcerative colitis. There was a statistically non-significant reduction in requirement for corticosteroids. No studies evaluated requirement for other immunosuppressive agents. For rheumatoid arthritis, omega-3 fatty acids had no effect on patient report of pain, swollen joint count, Erythrocyte Sedimentation Rate, and patient s global assessment. There was no effect on joint damage, contrary to a previous meta-analysis. There was a reduced requirement for anti-inflammatory drugs or corticosteroids. No studies assessed requirements for disease modifying antirheumatic drugs. For renal disease, omega-3 fatty acids had varying effects on serum creatinine and creatinine clearance. Single studies respectively demonstrated reduced progression to end-stage renal disease and improvements on hemodialysis graft patencyrelative. No studies assessed requirements for corticosteroids or other immunosuppressive drugs. v

7 For SLE, omega-3 fatty acids had variable effects on clinical activity. No studies assessed the effect on end organ damage, patient perception of disease, or requirements for other immunosuppressive drugs. One study showed no effect on corticosteroid requirements. For bone mineral density, the effect of omega-3 fatty acids was variable. No studies assessed the effect on fracture. Conclusions: The evidence for effects of omega-3 fatty acids on outcomes in the conditions assessed varies greatly. Omega-3 fatty acids appear to reduce serum triglycerides among type II diabetics, but have no effect on total cholesterol, HDL cholesterol, and LDL cholesterol. There appears to be no effect on most clinical outcomes in rheumatoid arthritis, although tender joint count may be reduced. There are insufficient data to draw conclusions about IBD, renal disease, SLE, bone density or fractures, requirement for anti-inflammatory or immunosuppressive drugs, or insulin resistance among type II diabetics. vi

8 Contents Evidence Report Chapter 1. Introduction... 1 The Recognition of Essential Fatty Acids... 1 Fatty Acid Nomenclature... 1 Fatty Acid Metabolism... 2 Physiological Functions of EPA and AA... 3 Dietary Sources and Requirements... 4 Rationale for and Organization of this Report... 9 Chapter 2. Methodology...11 Objectives...11 Scope of Work...11 Original Proposed Key Question...11 Technical Expert Panel...12 Key Questions Addressed in this Report...12 Diabetes...12 Inflammatory Bowel Disease...13 Rheumatoid Arthritis...13 Renal Disease...14 Systemic Lupus Erythematosus...14 Bone Density/Osteoporosis...14 Assessment of Adverse Events...14 Identification of Literature Sources...15 Evaluation of Evidence...16 Extraction of Data...16 Grading Evidence...16 Methodologic Quality of Randomized Controlled Trials...16 Applicability...17 Data Synthesis...17 Meta-Analysis...17 Selection of Trials for Descriptive Analysis or Meta-Analysis...17 Trial Summary Statistics...18 Stratification of Trials...19 Performance of Meta-Analysis...19 Sensitivity Analysis...19 Publication Bias...20 Interpretation of the Results...20 Peer Review...20 Chapter 3. Results...21 Results of Literature Search Diabetes Diabetes: Total Cholesterol vii

9 Diabetes: HDL Cholesterol Diabetes: LDL Cholesterol Diabetes: Triglycerides Diabetes: Insulin Sensitivity/Glycemic Control Inflammatory Bowel Disease Inflammatory Bowel Disease: Clinical Effect Inflammatory Bowel Disease: Effect on Requirement for Steroids/Other Immunosuppresive Drugs Rheumatoid Arthritis Rheumatoid Arthritis: Pain Rheumatoid Arthritis: Swollen Joints Rheumatoid Arthritis: Disease Activity (ESR) Rheumatoid Arthritis: Patient s Global Assessment Rheumatoid Arthritis: Joint Damage Rheumatoid Arthritis: Tender Joint Count Rheumatoid Arthritis: Effect on Anti-Inflammatory/Immunosuppressive Drug Requirement Renal Disease Renal Disease: Clinical Effect Renal Disease: Effect on Corticosteroid/Other Immunosuppressive Drug Requirement Systemic Lupus Erythematosus Systemic Lupus Erythematosus: Clinical Effect Systemic Lupus Erythematosus: Effect on Steroid/Other Immunosuppressive Drug Requirement Bone Density/Osteoporosis Bone Density/Osteoporosis: Clinical Effect Publication Bias Adverse Events Chapter 4. Discussion Overview..61 Main Findings..61 Conclusions..63 Future Research 63 References and Included Studies Listing of Excluded Studies Acronyms Tables Table 1.1 Nomenclature of Omega-3 Fatty Acids...2 viii

10 Table 1.2 Sources and Proportions of Omega-3 Fatty Acids in Common Foods and Supplements...6 Table 1.3 Good Food Sources of Omega-3 Fatty Acids...7 Table 1.4 Estimates of the Mean Intake of LA, ALA, EPA, and DHA in the U.S. Population from Analysis of NHANES III Data...8 Table 1.5 Mean, Range, and Median Usual Daily Intakes (Ranges) of n-6 and n-3 PUFAs in the U.S. Population, from Analysis of CSFII Data (1994 to 1998)...8 Table 1.6 The Omega-3 Fatty Acid Content, in Grams per 100 g Food Serving, of a Representative Sample of Commonly Consumed Fish, Shellfish, and Fish Oils, and Nuts and Seeds, and Plant Oils that Contain at Least 5 g Omega-3 Fatty Acids per 100 g...10 Table 3.1 Diabetes: Mean Difference for Total Cholesterol...24 Table 3.2 Relationship between Methodologic Quality and Applicability for Estimates of Effect of Omega-3 Fatty Acid Consumption on Total Cholesterol among People with Type II Diabetes...24 Table 3.3 Diabetes: Mean Difference for High-Density Lipoprotein (HDL)...27 Table 3.4 Relationship between Methodologic Quality and Applicability for Estimates of Effect of Omega-3 Fatty Acid Consumption on HDL among People with Type II Diabetes...27 Table 3.5 Diabetes: Mean Difference for Low-Density Lipoprotein (LDL)...30 Table 3.6 Relationship between Methodologic Quality and Applicability for Estimates of Effect of Omega-3 Fatty Acid Consumption on LDL among People with Type II Diabetes...30 Table 3.7 Diabetes: Mean Difference for Triglycerides...33 Table 3.8 Relationship between Methodologic Quality and Applicability for Estimates of Effect of Omega-3 Fatty Acid Consumption on Triglycerides among People with Type II Diabetes...33 Table 3.9 Diabetes: Mean Difference of Fasting Blood Glucose...36 Table 3.10 Relationship between Methodologic Quality and Applicability for Estimates of Effect of Omega-3 Fatty Acid Consumption on Fasting Blood Sugar among People with Type II Diabetes...37 Table 3.11 Diabetes: Effect Size of Hemoglobin A1c (HbA1c)...38 Table 3.12 Relationship between Methodologic Quality and Applicability for Estimates of Effect of Omega-3 Fatty Acid Consumption on Glycosylated Hemoglobin among People with Type II Diabetes...38 Table 3.13 Ulcerative Colitis Disease: Relative Risk of Relapse...41 Table 3.14 Relationship between Methodologic Quality and Applicability for Estimates of Effect of Omega-3 Fatty Acid Consumption with Ulcerative Colitis Disease for Relapse/Remission...42 Table 3.15 RA: Effect Size for Patient Assessment of Pain...44 Table 3.16 Relationship between Methodologic Quality and Applicability for Estimates of Effect of Omega-3 Fatty Acid Consumption on Pain among People with Rheumatoid Arthritis...45 Table 3.17 RA: Effect Size for Swollen Joint Count...47 ix

11 Table 3.18 Relationship between Methodologic Quality and Applicability for Estimates of Effect of Omega-3 Fatty Acid Consumption on Swollen Joints among People with Rheumatoid Arthritis...47 Table 3.19 RA: Effect Size for ESR...50 Table 3.20 Relationship between Methodologic Quality and Applicability for Estimates of Effect of Omega-3 Fatty Acid Consumption of ESR among People with Rheumatoid Arthritis...51 Table 3.21 RA: Effect Size for Patient Global Assessment...53 Table 3.22 Relationship between Methodologic Quality and Applicability for Estimates of Effect of Omega-3 Fatty Acid Consumption on Global Assessment among People with Rheumatoid Arthritis...53 Table 3.23 Summary of Reported Adverse Events...59 Figures Figure 1.1 Classical Omega-3 and Omega-6 Fatty Acid Synthesis Pathways and the Role of Omega-3 Fatty Acid in Regulating Health/Disease Markers...5 Figure 3.1 Literature Flow...22 Figure 3.2 Diabetes: Total Cholesterol...25 Figure 3.3 Diabetes: High Density Lipoprotein (HDL)...28 Figure 3.4 Diabetes: Low Density Lipoprotein (LDL)...31 Figure 3.5 Diabetes: Triglycerides...34 Figure 3.6 Diabetes: Fasting Blood Glucose...37 Figure 3.7 Diabetes: Hemoglobin A1c (HgA1c)...39 Figure 3.8 Ulcerative Colitis Disease: Relative Risk of Relapse...42 Figure 3.9 RA: Patient Assessment of Pain...45 Figure 3.10 RA: Swollen Joint Count...48 Figure 3.11 RA: ESR...51 Figure 3.12 RA: Patient Global Assessment...54 Appendices and Evidence Tables are provided electronically at x

12 Agency for Healthcare Research and Quality Evidence Report/Technology Assessment Number 89 Effects of Omega-3 Fatty Acids on Lipids and Glycemic Control in Type II Diabetes and the Metabolic Syndrome and on Inflammatory Bowel Disease, Rheumatoid Arthritis, Renal Disease, Systemic Lupus Erythematosus, and Osteoporosis Summary Introduction This report was requested and funded by the Office of Dietary Supplements, National Institutes of Health. It is one of several reports focusing on the role of omega-3 fatty acids in the prevention or treatment of various diseases. Three Evidence-based Practice Centers (EPCs) produced this series of reports: the Southern California EPC, based at RAND, the Tufts-New England Medical Center EPC, and the University of Ottawa EPC. This particular report focuses on the effects of omega-3 fatty acids on immunemediated diseases, bone metabolism, and gastrointestinal/renal diseases. Over the past 40 years, an increasing number of physiological functions have been attributed to omega-3 fatty acids, including movement of calcium and other substances into and out of cells, relaxation and contraction of muscles, inhibition and promotion of clotting, regulation of secretion of substances that include digestive enzymes and hormones, control of fertility, cell division, and growth. 1 In addition, omega-3 fatty acids may play an important role in brain development and function. Some evidence has suggested that omega-3 fatty acids in the diet may protect against heart attack and stroke, as well as certain inflammatory diseases like arthritis, lupus, and asthma. 1 The major dietary sources of omega- 3 fatty acids in the U.S. population are fish, fish oil, vegetable oils (principally canola and soybean), walnuts, wheat germ, and some dietary supplements. Methods Key Questions We consulted with three technical expert panels (TEPs) on this project. The respective panels focused on the following conditions: Rheumatoid arthritis, systemic lupus erythematosis (SLE), and bone density/osteoporosis Renal disease and diabetes Gastrointestinal diseases The TEPs advised us on refining the preliminary questions posed to us by AHRQ, determining the proper inclusion/exclusion criteria for the study and the populations of interest, establishing the proper outcomes measures, and conducting the appropriate analyses. Based on the original questions that we received from AHRQ and input from our TEPs, we addressed the following questions in this study: Diabetes What is the evidence in adults or children with a) type II diabetes, or b) insulin resistance/the metabolic syndrome for an effect of omega-3 fatty acids on: Total cholesterol HDL cholesterol LDL cholesterol Triglycerides U.S. DEPARTMENT OF HEALTH AND HUMAN SERVICES Public Health Service

13 What is the evidence in adults and children for an effect of omega-3 fatty acids on insulin sensitivity in a) type II diabetes, or b) the metabolic syndrome? Inflammatory Bowel Disease What is the evidence for the efficacy of omega-3 fatty acids in treatment of Crohn s disease and ulcerative colitis? What is the evidence in adults or children with inflammatory bowel disease that omega-3 fatty acids can replace steroids or other immunosuppressive drugs? What is the evidence that the benefits of omega-3 fatty acids are influenced by the concomitant administration of various immunosuppressive agents in the treatment of inflammatory bowel disease? Rheumatoid Arthritis What is the evidence in adults or children with rheumatoid arthritis that omega-3 fatty acids affect: Pain Number of swollen joints Disease activity Patients global assessment Joint damage What is the evidence in adults or children with rheumatoid arthritis that omega-3 fatty acids can replace other more potent anti-inflammatory or immunosuppressive drugs such as steroids and nonsteroidal anti-inflammatory drugs? What is the evidence that the benefits of omega-3 fatty acids are influenced by the concomitant administration of various immunosuppressive agents in the treatment of rheumatoid arthritis? Renal Disease What is the evidence for the efficacy of omega-3 fatty acids in treatment of renal inflammation and glomerulosclerosis? What is the evidence in adults or children with immunemediated renal disease that omega-3 fatty acids can replace steroids or other immunosuppressive drugs? What is the evidence that the benefits of omega-3 fatty acids are influenced by the concomitant administration of various immunosuppressive agents in the treatment of immunemediated renal disease? Systemic Lupus Erythematosus What is the evidence in adults or children with SLE that omega-3 fatty acids affect disease activity, damage, or patient perceptions of outcomes in SLE? What is the evidence in adults or children with SLE that omega-3 fatty acids can replace steroids or other immunosuppressive drugs? What is the evidence that the benefits of omega-3 fatty acids in the treatment of SLE are influenced by the concomitant administration of various immunosuppressive agents? Bone Density/Osteoporosis What is the evidence that omega-3 fatty acids help maintain bone mineral status? For each of the study questions, we also assessed: The effect of omega-3 fatty acids on subpopulations The effects of covariates, dose, source, and exposure duration on the outcomes of interest The sustainment of effect In addition to answering these questions, we evaluated the data on adverse events, including clinical bleeding, gastrointestinal complaints or nausea, diarrhea, headache, dermatological problems, and withdrawal from study due to an adverse event. Search Strategy We searched the following online databases to identify literature: MEDLINE (1966-July 2003), PreMEDLINE (July 8, 2003), EMBASE (1980-Week 27, 2003), Cochrane Central Register of Controlled Trials (2nd Quarter, 2003), CAB Health (1973-June 2003), and Dissertation Abstracts (1861-December 2002). We developed a core search strategy and applied it to each relevant disease category: rheumatoid arthritis, bone density, SLE, renal disease, diabetes, and gastrointestinal diseases. We also reviewed the reference lists of all applicable articles and contacted our technical expert panel as well as industry experts to identify unpublished data. Selection Criteria Two reviewers independently reviewed each article considered for inclusion in the study. Any disagreements between the reviewers were resolved through consensus. We included any articles pertaining to the effects of omega-3 fatty acids on diabetes mellitus, inflammatory bowel disease (ulcerative colitis and Crohn s disease), rheumatoid arthritis, SLE, renal disease, osteoporosis, or bone mineral status. We included only articles that presented research on human subjects and those that reported the results of randomized clinical trials or controlled clinical trials; we accepted observational studies only for bone mineral status. Language was not a barrier to inclusion. Data Extraction and Analysis For each article included in the study, two reviewers independently extracted data about the trial design; the outcomes of interest; the quality of the trial; the number and characteristics of the patients; details on the intervention, such 2

14 as the dose, frequency, and duration; the types of outcome measures; adverse events; and the elapsed time between the intervention and outcome measurements. Any disagreements between the reviewers were resolved through consensus. For each article, we then evaluated the quality of the design and execution of trials using a system developed by Jadad; determined a combined applicability grade based on applicability to the U.S. population and health state; performed a meta-analysis of those studies that sufficiently assessed interventions, populations, and outcomes to justify pooling; and performed a qualitative analysis of the remaining studies. Results We screened 4,212 article titles. From these article titles, we reviewed the 1,097 full-text articles relevant to our topics. Of these full-text articles, 115 met our selection criteria and underwent detailed review; among these, 83 articles met our inclusion criteria (34 for diabetes/metabolic syndrome, 13 for inflammatory bowel disease, 21 for rheumatoid arthritis, 9 for renal disease, 3 for SLE, and 4 for bone density and fractures). All of these 83 articles were randomized controlled trials, except for one observational study of bone density. We had a sufficient number of articles to perform quantitative meta-analyses for rheumatoid arthritis, inflammatory bowel disease, and diabetes. Due to the limited number of articles we identified for renal failure, SLE, and bone mineral metabolism, we performed qualitative analyses for these conditions. Overall, our analyses yielded variable results both within and among disease categories. Our findings are summarized for each condition studied. Diabetes/Metabolic Syndrome. Among 18 studies of type II diabetes or the metabolic syndrome, omega-3 fatty acids had a favorable effect on triglyceride levels relative to placebo (pooled random effects estimate: ; 95% CI, , ) but had no effect on total cholesterol, HDL cholesterol, LDL cholesterol, fasting blood sugar, or glycosylated hemoglobin, by meta-analysis. Omega-3 fatty acids had no effect on plasma insulin or insulin resistance in type II diabetics or patients with the metabolic syndrome, by qualitative analysis of four studies. Inflammatory Bowel Disease. Among 13 studies reporting outcomes in patients with inflammatory bowel disease, variable effects of omega-3 fatty acids on clinical score, sigmoidoscopic score, histologic score, induced remission, and relapse were reported. In ulcerative colitis, omega-3 fatty acids had no effect on the relative risk of relapse in a meta-analysis of three studies. There was a statistically non-significant reduction in requirement for corticosteroids for omega-3 fatty acids relative to placebo in two studies. No studies evaluated the effect of omega-3 fatty acids on requirement for other immunosuppressive agents. Rheumatoid Arthritis. Among nine studies reporting outcomes in patients with rheumatoid arthritis, omega-3 fatty acids had no effect on patient report of pain, swollen joint count, Erythrocyte Sedimentation Rate (ESR), and patient s global assessment by meta-analysis. A previously performed meta-analysis 2 reached the same conclusions for swollen joint count, ESR, and patient s global assessment. That metaanalysis found a statistically significant improvement in tender joint count compared to placebo (rate difference = -2.9, 95% CI, -3.8, -2.1). The one study that assessed the effect on joint damage found no effect. In a qualitative analysis of seven studies that assessed the effect of omega-3 fatty acids on antiinflammatory drug or corticosteriod requirement, six demonstrated reduced requirement for these drugs. No studies assessed the effect on requirements for disease modifying antirheumatic drugs. None of the studies used a composite score that incorporates both subjective and objective measures of disease activity, such as the American College of Rheumatology response criteria. Renal Disease. In a qualitative analysis of nine studies that assessed the effect of omega-3 fatty acids in renal disease, there were varying effects on serum creatinine and creatinine clearance and no effect on progression to end stage renal disease. In a single study that assessed the effect on hemodialysis graft patency, graft patency was significantly better with fish oil than with placebo. No studies assessed the effects of omega-3 fatty acids on requirements for corticosteroids Systemic Lupus Erythematosis. Among three studies that assessed the effects of omega-3 fatty acids in SLE, variable effects on clinical activity were reported. No studies were identified that assessed effect on damage or patient perception of disease. Omega-3 fatty acids had no effect on corticosteroid requirements in one study. No studies were identified that assessed the effects of omega-3 fatty acids on requirements for other immunosuppressive drugs for SLE. None of the studies used a measure of disease activity that incorporates both subjective and objective measures of disease activity. Bone Mineral Density/Fracture. Among five studies described in four reports the effect of omega-3 fatty acids on bone mineral density was variable. No studies that assessed the effect of omega-3 fatty acids on fracture were identified. The quantity and strength of evidence for effects of omega-3 fatty acids on outcomes in the conditions assessed varies greatly. The findings of many studies among type II diabetics provide strong evidence that omega-3 fatty acids reduce serum triglycerides but have no effect on total cholesterol, HDL cholesterol, and LDL cholesterol. For rheumatoid arthritis, the available evidence suggests that omega-3 fatty acids reduce tender joint counts and may reduce requirements for corticosteroids, but does not support an effect of omega-3 fatty acids on other clinical outcomes. There are insufficient data available to draw conclusions about the effects of omega-3 fatty 3

15 acids on inflammatory bowel disease, renal disease, SLE, bone density, or fractures or the effects of omega-3 fatty acids on insulin resistance among type II diabetics. Discussion We offer the following observations and recommendations regarding future research on the effects of omega-3 fatty acids on lipids and glycemic control in type II diabetes and the metabolic syndrome and on inflammatory bowel disease, rheumatoid arthritis, renal disease, SLE, and osteoporosis. Additional research on the effects of omega-3 fatty acids needs to be performed on inflammatory bowel disease, renal disease, SLE, bone density, or fractures or the effects of omega-3 fatty acids on insulin resistance among type II diabetics before recommendations regarding the use of omega-3 fatty acids for these conditions can be made. Studies of inflammatory bowel disease that include patients with both Crohn s disease and ulcerative colitis should report data separately for these groups. Studies that assess the effects of omega-3 fatty acids should use standard validated instruments to assess clinical outcomes. Trials that assess the effects of omega-3 fatty acids should be designed to evaluate the effect of source, dose, treatment duration, and the sustainment of effect after discontinuation of omega-3 fatty acid consumption. Studies of omega-3 fatty acids should explicitly define both the quantity of the omega-3 fatty acid source and of the specific omega-3 fatty acids present in a study dose of that source. Trials of omega-3 fatty acids should include a baseline assessment of dietary omega-3 and omega-6 fatty acid intake. In controlled trials that assess the effects of omega-3 fatty acids, analysis should include and report explicit testing of the effects of the omega-3 fatty acid relative to the control substance. In studies that use a crossover design, outcome data for all study arms should be reported at the end of each treatment period. Availability of the Full Report The full evidence report from which this summary was taken was prepared for the Agency for Healthcare Research and Quality (AHRQ) by the Southern California/RAND Evidencebased Practice Center, Los Angeles, CA, under Contract No The full report is expected to be available in March At that time, printed copies may be obtained free of charge from the AHRQ Publications Clearinghouse by calling Requesters should ask for Evidence Report/Technology Assessment No. 89, Effects of Omega-3 Fatty Acids on Lipids and Glycemic Control in Type II Diabetes and the Metabolic Syndrome and on Inflammatory Bowel Disease, Rheumatoid Arthritis, Renal Disease, Systemic Lupus Erythematosus, and Osteoporosis. In addition, Internet users will be able to access the report and this summary online through AHRQ s Web site at Suggested Citation MacLean CH, Mojica WA, Morton SC, Pencharz J, Hasenfeld Garland R, Tu W, Newberry SJ, Jungvig LK, Grossman J, Khanna P, Rhodes S, Shekelle P. Effects of Omega- 3 Fatty Acids on Lipids and Glycemic Control in Type II Diabetes and the Metabolic Syndrome and on Inflammatory Bowel Disease, Rheumatoid Arthritis, Renal Disease, Systemic Lupus Erythematosus, and Osteoporosis. Summary, Evidence Report/Technology Assessment No. 89. (Prepared by the Southern California/RAND Evidence-based Practice Center, Los Angeles, CA.) AHRQ Publication No. 04-E Rockville, MD: Agency for Healthcare Research and Quality. March References 1. Innis S. Essential dietary lipids. In: Ziegler EE, Filer, LJ Jr, editors. Present knowledge in nutrition. Washington, DC: International Life Sciences Institute; Fortin P, Lew R, Liang M, et al. Validation of a meta-analysis: The effects of fish oil in rheumatoid arthritis. J Clin Epidemiol 1995;48(11): AHRQ Pub. No. 04-E012-1 March 2004 ISSN X

16 Evidence Report

17 Chapter 1. Introduction This report is one of a group of evidence reports prepared by three Agency for Healthcare Research and Quality (AHRQ)-funded Evidence-Based Practice Centers (EPCs) on the role of omega-3 fatty acids (both from food sources and from dietary supplements) in the prevention or treatment of a variety of diseases. These reports were requested and funded by the Office of Dietary Supplements, National Institutes of Health. The three EPCs the Southern California EPC (SCEPC, based at RAND), the Tufts-New England Medical Center (NEMC) EPC, and the University of Ottawa EPC have each produced evidence reports. To ensure consistency of approach, the three EPCs collaborated on selected methodological elements, including literature search strategies, rating of evidence, and data table design. The aim of these reports is to summarize the current evidence on the effects of omega-3 fatty acids on prevention and treatment of cardiovascular diseases, cancer, child and maternal health, eye health, gastrointestinal/renal diseases, asthma, immune-mediated diseases, tissue/organ transplantation, mental health, and neurological diseases and conditions. In addition to informing the research community and the public on the effects of omega-3 fatty acids on various health conditions, it is anticipated that the findings of the reports will also be used to help define the agenda for future research. This report focuses on the effects of omega-3 fatty acids on immune-mediated diseases, bone metabolism, and gastrointestinal/renal diseases. Subsequent reports from the SCEPC will focus on cancer and neurological diseases and conditions. This chapter provides a brief review of the current state of knowledge about the metabolism, physiological functions, and sources of omega-3 fatty acids. The Recognition of Essential Fatty Acids Dietary fat has long been recognized as an important source of energy for mammals, but in the late 1920s, researchers demonstrated the dietary requirement for particular fatty acids, which came to be called essential fatty acids. It was not until the advent of intravenous feeding, however, that the importance of essential fatty acids was widely accepted: Clinical signs of essential fatty acid deficiency are generally observed only in patients on total parenteral nutrition who received mixtures devoid of essential fatty acids or in those with malabsorption syndromes. These signs include dermatitis and changes in visual and neural function. Over the past 40 years, an increasing number of physiological functions, such as immunomodulation, have been attributed to the essential fatty acids and their metabolites, and this area of research remains quite active. 1, 2 Fatty Acid Nomenclature The fat found in foods consists largely of a heterogeneous mixture of triacylglycerols (triglycerides)--glycerol molecules that are each combined with three fatty acids. The fatty acids can be divided into two categories, based on chemical properties: saturated fatty acids, which are usually solid at room temperature, and unsaturated fatty acids, which are liquid at room Note: Appendixes and Evidence Tables are provided electronically at 1

18 temperature. The term saturation refers to a chemical structure in which each carbon atom in the fatty acyl chain is bound to (saturated with) four other atoms, these carbons are linked by single bonds, and no other atoms or molecules can attach; unsaturated fatty acids contain at least one pair of carbon atoms linked by a double bond, which allows the attachment of additional atoms to those carbons (resulting in saturation). Despite their differences in structure, all fats contain approximately the same amount of energy (37 kilojoules/gram, or 9 kilocalories/gram). The class of unsaturated fatty acids can be further divided into monounsaturated and polyunsaturated fatty acids. Monounsaturated fatty acids (the primary constituents of olive and canola oils) contain only one double bond. Polyunsaturated fatty acids (PUFAs) (the primary constituents of corn, sunflower, flax seed and many other vegetable oils) contain more than one double bond. Fatty acids are often referred to using the number of carbon atoms in the acyl chain, followed by a colon, followed by the number of double bonds in the chain (e.g., 18:1 refers to the 18-carbon monounsaturated fatty acid, oleic acid; 18:3 refers to any 18-carbon PUFA with three double bonds). PUFAs are further categorized on the basis of the location of their double bonds. An omega or n notation indicates the number of carbon atoms from the methyl end of the acyl chain to the first double bond. Thus, for example, in the omega-3 (n-3) family of PUFAs, the first double bond is 3 carbons from the methyl end of the molecule. The trivial names, chemical names and abbreviations for the omega-3 fatty acids are detailed in Table 1.1. Finally, PUFAs can be categorized according to their chain length. The 18-carbon n-3 and n- 6 short-chain PUFAs are precursors to the longer 20- and 22-carbon PUFAs, called long-chain PUFAs (LCPUFAs). Table 1.1. Nomenclature of omega-3 fatty acids. Names Abbreviations Trivial IUPAC* Carboxyl-reference Omega-reference Other Linolenic acid 9,12,15-octadecenoic acid 18: :3n-3 18:3 (ω-3) ALA α-la LNA α-lna Docosahexaenoic acid 4,8,12,15,19- docosahexaenoic 22: :6n-3 DHA acid 22:6 (ω-3) Docosapentaenoic acid 7,10,13,16,19- docosapentaenoic acid 22: :5n-3 22:5 (ω-3) DPA Eicosapentaenoic acid Icosapentaenoic acid Timnodonic acid 5,8,11,14,17- eicosapentaenoic acid *IUPAC=International Union of Pure and Applied Chemistry 20: :5n-3 20:5 (ω-3) EPA Fatty Acid Metabolism Mammalian cells can introduce double bonds into all positions on the fatty acid chain except the n-3 and n-6 position. Thus, the short-chain alpha-linolenic acid (ALA, chemical abbreviation: 18:3n-3) and linoleic acid (LA, chemical abbreviation: 18:2n-6) are essential fatty acids. No other fatty acids found in food are considered essential for humans, because they can all be synthesized from the short chain fatty acids. 2

19 Following ingestion, ALA and LA can be converted in the liver to the long chain, moreunsaturated n-3 and n-6 LCPUFAs by a complex set of synthetic pathways that share several enzymes (Figure 1). LC PUFAs retain the original sites of desaturation (including n-3 or n-6). The omega-6 fatty acid LA is converted to gamma-linolenic acid (GLA, 18:3n-6), an omega- 6 fatty acid that is a positional isomer of ALA. GLA, in turn, can be converted to the longerchain omega-6 fatty acid, arachidonic acid (AA, 20:4n-6). AA is the precursor for certain classes of an important family of hormone-like substances called the eicosanoids (see below). The omega-3 fatty acid ALA (18:3n-3) can be converted to the long-chain omega-3 fatty acid, eicosapentaenoic acid (EPA; 20:5n-3). EPA can be elongated to docosapentaenoic acid (DPA 22:5n-3), which is further desaturated to docosahexaenoic acid (DHA; 22:6n-3). EPA and DHA are also precursors of several classes of eicosanoids and are known to play several other critical roles, some of which are discussed further below. The conversion from parent fatty acids into the LC PUFAs - EPA, DHA, and AA - appears to occur slowly in humans. In addition, the regulation of conversion is not well understood, although it is known that ALA and LA compete for entry into the metabolic pathways. Physiological Functions of EPA and AA As stated earlier, fatty acids play a variety of physiological roles. The specific biological functions of a fatty acid are determined by the number and position of double bonds and the length of the acyl chain. Both EPA (20:5n-3) and AA (20:4n-6) are precursors for the formation of a family of hormone- like agents called eicosanoids. Eicosanoids are rudimentary hormones or regulating - molecules that appear to occur in most forms of life. However, unlike endocrine hormones, which travel in the blood stream to exert their effects at distant sites, the eicosanoids are autocrine or paracrine factors, which exert their effects locally in the cells that synthesize them or adjacent cells. Processes affected include the movement of calcium and other substances into and out of cells, relaxation and contraction of muscles, inhibition and promotion of clotting, regulation of secretions including digestive juices and hormones, and control of fertility, cell division, and growth. 3 The eicosanoid family includes subgroups of substances known as prostaglandins, leukotrienes, and thromboxanes, among others. As shown in Figure 1.1, the long-chain omega-6 fatty acid, AA (20:4n-6), is the precursor of a group of eicosanoids that include series-2 prostaglandins and series-4 leukotrienes. The omega-3 fatty acid, EPA (20:5n-3), is the precursor to a group of eicosanoids that includes series-3 prostaglandins and series-5 leukotrienes. The AA-derived series-2 prostaglandins and series-4 leukotrienes are often synthesized in response to some emergency such as injury or stress, whereas the EPA-derived series-3 prostaglandins and series-5 leukotrienes appear to modulate the effects of the series-2 prostaglandins and series-4 leukotrienes (usually on the same target cells). More specifically, the series-3 prostaglandins are formed at a slower rate and work to attenuate the effects of excessive levels of series-2 prostaglandins. Thus, adequate production of the series-3 prostaglandins seems to protect against heart attack and stroke as well as certain inflammatory diseases like arthritis, lupus, and asthma. 3 EPA (22:6 n-3) also affects lipoprotein metabolism and decreases the production of substances including cytokines, interleukin 1ß (IL-1ß), and tumor necrosis factor a (TNF-a) 3

20 that have pro-inflammatory effects (such as stimulation of collagenase synthesis and the expression of adhesion molecules necessary for leukocyte extravasation [movement from the circulatory system into tissues]). 2 The mechanism responsible for the suppression of cytokine production by omega-3 LC PUFAs remains unknown, although suppression of omega-6-derived eicosanoid production by omega-3 fatty acids may be involved, because the omega-3 and omega- 6 fatty acids compete for a common enzyme in the eicosanoid synthetic pathway, delta-6 desaturase. DPA (22:5n-3) (the elongation product of EPA) and its metabolite DHA (22:6n-3) are frequently referred to as very long chain n-3 fatty acids (VLCFA). Along with AA, DHA is the major PUFA found in the brain and is thought to be important for brain development and function. Recent research has focused on this role and the effect of supplementing infant formula with DHA (since DHA is naturally present in breast milk but not in formula). Dietary Sources and Requirements Both ALA and LA are present in a variety of foods. LA is present in high concentrations in many commonly used oils, including safflower, sunflower, soy, and corn oil. ALA is present in some commonly used oils, including canola and soybean oil, and in some leafy green vegetables. Thus, the major dietary sources of ALA and LA are PUFA-rich vegetable oils. The proportion of LA to ALA as well as the proportion of those PUFAs to others varies considerably by the type of oil. With the exception of flaxseed, canola, and soybean oil, the ratio of LA to ALA in vegetable oils is at least 10 to 1. The ratios of LA to ALA for flaxseed, canola, and soy are approximately 1: 3.5, 2:1, and 8:1, respectively; however, flaxseed oil is not typically consumed in the North American diet. It is estimated that on average in the U.S., LA accounts for 89% of the total PUFAs consumed, and ALA accounts for 9%. Another estimate suggests that Americans consume 10 times more omega-6 than omega-3 fatty acids. 4 Table 1.2 shows the proportion of omega 3 fatty acids for a number of foods. 4

21 Figure 1.1. Classical omega-3 and omega-6 fatty acid synthesis pathways and the role of omega-3 fatty acid in regulating health/disease markers. Polyunsaturated Fatty Acids (PUFAs) Omega-6 Large intake (7-8% dietary energy)* Omega-3 Series-1 Prostaglandins: TXA 1 PGE 1 PGF 1a Linoleic acid (LA) 18:2 n-6 (Sunflower, soy, cottonseed, safflower oils) Delta-6 Desaturase (D6D) Minor intake ( % dietary energy)* *The dietary intake levels are based on approximate current levels in North American diets PGD 1 Gamma-linolenic acid (GLA) 18:3 n-6 (Evening primrose, borage, black currant oils) Alpha-Linolenic acid (ALA) 18:3 n-3 (Canola, Soybean, and Flaxseed oils, grains, green vegetables) Eicosanoids Series-2 Prostaglandins: TXA 2 PGE 2 PGF 2a PGD 2 PGH 2 PGL 2 Elongase Delta-6 Desaturase (D6D) Octadecatetranenoic acid 18:4 n-3 Series-4 Leukotrienes Series-3 Prostaglandins: PGE 3 PGH 3 PGI 3 TXA 3 Series-5 Leukotrienes Dihomo-gamma-linolenic acid (DGLA) 20:3 n-6 (Liver & other organ meats) Arachidonic acid (AA) 20:4 n-6 (Animal fats, brain, organ meats, egg yolk) Delta-5 desaturase (D5D) Elongase Eicosatetraenoic acid 20:4 n-3 Eicosapentaenoic acid (EPA) 20:5 n-3 (Fish liver oils, fish eggs) TNF-alpha IL-1 beta suppress amino acids DNA Thromboxanes (TX) are important for: - blood clotting - constricting blood vessels - inflammatory function of white blood cells Leukotrienes are important for: - inflammation - lung function Prostaglandins (PG) are important for: - pregnancy, birth - stomach function - kidney function - maintaining blood vessel patency - preventing blood clots - inflammation, response to infection Adrenic acid 22:4 n-6 Docosapentaenoic acid (DPA) 22:5 n-6 Docosapentaenoic acid (DPA) 22:5 n-3 24:4 n-6 24:5 n-3 24:5 n-6 24:6 n-3 Beta-oxidation Elongase Elongase D6D Beta-oxidation Docosahexaenoic acid (DHA) 22:6 n-3 (Human milk, egg yolks, fish liver oils, fish eggs, liver, brain, other organ meats) Lower VLDL, Apo B-100, Tg Extracellular Ca 2+ Endothelial and smooth muscle cells Adrenoceptors Cell membrane Intracellular Ca 2+ endoplasmic reticulum Energy metabolic pathway Beta-oxidation 5

22 Table 1.2. Sources and proportions of omega-3 fatty acids in common foods and supplements. Food/supplement EPA 20:5n-3 DHA 22:6n-3 DPA 22:5n-3 ALA 18:3n-3 Foods in which Total Omega-3 Fatty Acids account for more than 50% of Total PUFA Fish Anchovy U U U Halibut U U U Herring U U U Mackerel U U U U U U Salmon U U Sardine U Tuna U U Canned, U waterpacked U U Fresh Bluefin Oils/Supplements Cod liver oils Coromega * Fish oil capsules* Flaxseed/linseed oil* Herring oil MaxEPA* Menhaden oil Neuromins* Omacor* Ropufa* Salmon oil Sardine oil U U U U U U U U U U U U U U U U U U U U U U U U U U U U Seeds Flaxseeds/Linseeds Oils Foods/Supplements in which total Omega 3 fatty acids are 10-50% of total PUFA Black currant oil Canola oil** Mustard seed oils Soybean oil Walnut oil Wheat germ oil Other foods Wheat germ Human milk Foods/Supplements in which total Omega 3 fatty acids are less than 10% of total PUFA Efamol Marine* U U Soybeans Walnuts U U * Dietary Supplement ** Also called rapeseed oil U U U U U U U U U 6

23 Several lines of research have suggested that the high ratio of omega 6s to omega 3s currently consumed in the U.S. promotes a number of chronic diseases. 4 Because of the slow rate of elongation and further desaturation of the essential FA, the importance of LC PUFAs to many physiological processes, and the overwhelming ratio of omega 6s to omega 3s in the average U.S. diet, nutrition experts are increasingly recognizing the need for humans to augment the body s synthesis of omega 3 LC PUFAs by consuming foods that are rich in these compounds. According to data from two population-based surveys, the major dietary sources of LC omega-3 fatty acids in the U.S. population are fish, fish oil, vegetable oils (principally canola and soybean), walnuts, wheat germ, and some dietary supplements, and the primary dietary sources of omega-6 LC PUFAs are meats and dairy products. These surveys, the Continuing Food Survey of Intakes by Individuals (CSFII) and the third National Health and Nutrition Examination (NHANES III) surveys, are the main sources of dietary intake data for the U.S. population. The CSFII has the advantage of collecting dietary recall data over a period of several days, which may permit estimates of omega-3 intake that more accurately reflect individual intakes than do those of NHANES. However, NHANES intake data have the advantage of being able to be linked to health outcomes. Table 1.3 provides a list of food sources of omega-3 fatty acids. Table 1.3. Good food sources* of omega 3 fatty acids. EPA+DHA ALA EPA+DHA ALA Fish (3oz. Cooked) Oils (1 Tbs.) Anchovy U Canola U Halibut U Cod liver U Herring, Atlantic U Flaxseed/linseed U Pacific U Herring U Mackerel, Atlantic U Menhaden U Pacific U Salmon U Salmon, Atlantic** U Sardine U Sardines U Soybean U Trout, Rainbow U Walnut U Tuna, Albacore U Wheat germ U Canned light, water-packed Canned white, water-packed Fresh Bluefin U U U Organ Meats (3 oz. Cooked) Seeds Brain, lamb U Flaxseeds/linseeds (1 Tbs.) U Brain, pork U Thymus, calf U Other Foods Caviar (1 oz.)# U Human breast milk (1c)# U Soybeans, cooked (1/2c) U Tofu, regular (1/2c) U Walnuts (1/4c) U Wheat germ (1/4c)# U Source: Figures adapted from USDA, 2003; *Foods that provide (per serving) 10% or more of the Adequate Intake (AI) for ALA or the Acceptable Macronutrient Distribution Range (AMDR) for EPA and DHA (10% of the AMDR for ALA); an AI is a recommended average daily intake level based on observed or experimentally determined estimates of nutrient intake by a group of apparently healthy people (thus, assumed to be adequate) when an RDA cannot be determined; an AMDR is defined as a range of intakes for a particular energy source that is associated with reduced risk of chronic disease while providing adequate intake of essential nutrients. 5 # Standard serving size not established; **Farm-raised Atlantic salmon have nearly identical omega-3 fatty acid levels to wild Atlantic salmon and significantly more omega-3 fatty acids than wild Pacific salmon. 7

24 Table 1.4 shows the mean and median intakes of omega-3 and omega-6 fatty acids reported by NHANES III. 1 Table 1.5 shows the mean and median intakes of omega-3 and omega-6 fatty acids reported by CSFII. Table 1.4. Estimates of the mean intake of LA, ALA, EPA, and DHA in the U.S. Population from analysis of NHANES III data.* Grams/day Percent energy intake/day Mean ± SEM Median (range)** Mean ± SEM Median (range)** LA (18:2n-6) 14.1 ± (0-168) 5.79 ± (0-39.4) ALA (18:3n-3) 1.33 ± (0-17) 0.55 ± (0-4.98) EPA (20:5n-3) 0.04 ± (0-4.1) 0.02 ± (0-0.61) DHA (22:6n-3) 0.07 ± (0-7.8) 0.03 ± (0-2.86) *Based on analysis of a single 24-hour dietary recall from NHANES III data; **Distributions are not adjusted for the oversampling of Mexican Americans, non-hispanic African Americans, children 5 years old and under, and adults 60 years and over in the NHANES III dataset. Table 1.5. Mean, range, and median usual daily Intakes (ranges) of n-6 and n-3 PUFAs, in the U.S. population, from analysis of CSFII data (1994 to 1998).* Mean (gms/d) Range of Means (gms/d) Median (gms/d) (± SEM)** (± SEM)** (±SEM) LA (18:2n-6) 13.0 ± ± ± ± 0.1 Total n-3 FA 1.40 ± ± ± ± 0.01 ALA (18:3n-3) 1.30 ± ± ± ± 0.01 EPA (20:5n-3) DPA (22:5n-3) DHA (22:6n-3) ± < ± ± Source: Adapted from Dietary Reference Intakes Report; 5 *Estimates are based on respondents intakes on the first day of survey and were adjusted using the Iowa State University method; **For all individuals. Lacking sufficient evidence from research on the effects or correction of dietary deficiencies to establish Recommended Dietary Allowances (RDAs) for the essential fatty acids, the Food and Nutrition Board (FNB) of the Institute of Medicine 5 has set adequate intakes 2 (AI) for the essential fatty acids, based on the average intakes of healthy CSFII participants. The AIs for the essential fatty acids vary by age group and sex, as well as for particular conditions such as pregnancy and breastfeeding. For ALA, the AI for men 19 and older, is 1.6 grams/day and the AI for (non-pregnant, non-breastfeeding) women is 1.1 grams/day. The AI for LA is 17 grams/day for men and 11 grams/day for women. Based on evidence suggesting a role in prevention or treatment of some chronic diseases, the FNB has also established Acceptable Macronutrient Distribution Ranges (AMDR) for the essential fatty acids. An AMDR is defined as a range of intakes for a particular energy source that is associated with reduced risk of chronic disease while providing adequate intake of 1 The population represented by NHANES III includes individuals ages 2 months and older. Mexican Americans and non- Hispanic African-Americans, children 5 years old and younger, and adults 60 years of age and over were over-sampled to produce more precise estimates for these population groups. There were no imputations for missing 24-hour dietary recall data. A total of 29,105 participants had complete and reliable dietary recall data. The NHANES III also included a physical examination and health survey of each participant. 2 An Adequate Intake (AI) is defined as the recommended average daily intake level based on observed or experimentally determined approximations or estimates of nutrient intake, by a group (or groups) of apparently healthy people, that are assumed to be adequate used when a recommended dietary allowance cannot be determined. 5 An AI is set when data are insufficient or inadequate to establish an Estimated Average Requirement, on which the RDA is based, and indicate the need for more and better research. The EAR is the average daily nutrient intake level estimated to meet the requirement of half the healthy individuals in a particular life stage and gender group, based on a specific indicator or criterion of adequacy. 8

25 essential nutrients. 5 The AMDR is expressed as a percentage of total energy intake: The AMDR for LA is set at 5 to 10 percent of usual energy intake, and the AMDR for ALA is 0.6 to 1.2 percent of energy intake. Of this amount, up to 10 percent can be consumed as EPA and/or DHA, the omega-3 LC PUFAs. For a person who consumes 2000 kcal/day, ALA intake should range from 1.3 to 2.6 grams/day, and EPA/DHA intake can substitute for 0.13 to 0.26 of that quantity. Table 1.3 lists foods that provide 10 percent or more of these recommended intakes per serving, which may be referred to as good sources. 3 Table 1.6 provides the actual omega-3 content per 100 gm for a variety of foods. Rationale for and Organization of this Report Studies show that tissue levels of AA and EPA-derived eicosanoids influence many physiological processes, including platelet aggregation, vessel wall constriction, and immune cell function (IOM), resulting in protection against heart attack and stroke as well as certain inflammatory diseases like arthritis, systemic lupus erythematosus, and asthma. Epidemiological studies have suggested that groups of people who consume diets high in omega 3 FAs may experience a lower prevalence of these conditions, and many small trials have attempted to assess the effects of adding omega 3 fatty acids to the diet, either as omega-3 FA-rich foods or as dietary supplements (primarily fish oils). In addition, dietary omega 3FA have been found to increase calcium absorption, rates of bone formation, and bone strength in rodents and birds. In response to this evidence, a number of omega-3 FA-containing dietary supplements that claim to protect against a variety of conditions have appeared on the market. Thus, AHRQ and the NIH Office of Dietary Supplements have requested a synthesis of the research to date on the health effects of diets rich in omega-3 FA. The remainder of this report is organized into four chapters. Chapter Two describes the methods we used to identify and review studies related to the role of omega-3 fatty acids in immune-mediated diseases, bone metabolism, and gastrointestinal/renal diseases. Chapter Three presents our findings related to the effects of omega-3 fatty acids on those diseases/conditions. Chapter Four presents our conclusions and recommendations for future research in this area. 3 Identifying a food as a good source of a nutrient strictly means that one standard serving of the food supplies 10 to 19 percent of the Daily Value for that nutrient. The Daily Values are based on the FDA s Daily Reference Values, standards for the macronutrients (fats, protein, carbohydrates, and dietary fiber), which are similar, although not identical to the DRIs (RDAs) and are based on the amount of energy consumed per day (2000 kcal/d is the reference for calculating DVs). In the case of the PUFAs, no DVs have been established: For this report, the FNB s AIs and AMDRs, have been used instead. 9

26 Table 1.6. The omega-3 fatty acid content, in grams per 100 g food serving, of a representative sample of commonly consumed fish, shellfish, and fish oils, and nuts and seeds, and plant oils that contain at least 5 g omega-3 fatty acids per 100 g. Food item EPA DHA ALA Food item EPA DHA ALA Fish (Raw a ) Fish, continued Anchovy, European Tuna, Fresh, Yellowfin trace 0.2 trace Bass, Freshwater, Mixed Sp Tuna, Light, Canned in Oil e trace 0.1 trace Bass, Striped trace Tuna, Light, Canned in Water e trace 0.2 trace Bluefish Tuna, White, Canned in Oil e trace Carp Tuna, White, Canned in Water e trace Catfish, Channel trace Whitefish, Mixed Sp Cod, Atlantic trace 0.1 trace Whitefish, Mixed Sp., Smoked trace Cod, Pacific trace 0.1 trace Wolf fish, Atlantic trace Eel, Mixed Sp. trace trace 0.4 Flounder & Sole Sp. trace 0.1 trace Grouper, Mixed Sp. trace 0.2 trace Shellfish (Raw) Haddock trace 0.1 trace Abalone, Mixed Sp. trace - - Halibut, Atlantic and Pacific trace 0.3 trace Clam, Mixed Sp. trace trace trace Halibut, Greenland trace Crab, Blue Herring, Atlantic Crayfish, Mixed Sp., Farmed trace 0.1 trace Herring, Pacific trace Lobster, Northern Mackerel, Atlantic Mussel, Blue trace Mackerel, Pacific and Jack trace Oyster, Eastern, Farmed trace Mullet, Striped trace Oyster, Eastern, Wild trace Ocean Perch, Atlantic trace 0.2 trace Oyster, Pacific trace 10

27 Chapter 2. Methodology Objectives The topic of this report was nominated by the National Institutes of Health (NIH) Office of Dietary Supplements (ODS). The three participating Evidence-Based Practice Centers (EPCs) were asked to examine the effects of omega-3 fatty acids, in general, and on the following conditions: Cardiovascular Disease, Transplantation, Immune-Mediated Diseases, Gastrointestinal/Renal Diseases, Cancer, Neurology, Asthma, Child/Maternal Health, Eye Health, and Mental Health. The Southern California EPC (SCEPC) was responsible for examining Immune-Mediated Diseases and Gastrointestinal/Renal Diseases in Year 1 of the project and Cancer and Neurology in Year 2 of the project. Scope of Work The methodology that we used for this study included the following: Refining the preliminary questions provided by AHRQ, Convening a technical expert panel to advise the SCEPC on the study, Identifying sources of evidence in the scientific literature, Establishing inclusion/exclusion criteria for the articles identified in the scientific literature, Identifying potential evidence with attention to controlled clinical trials using omega- 3 fatty acids, Evaluating potential evidence for methodological quality and relevance, Extracting data from studies meeting methodological and clinical criteria, Synthesizing the results, Performing further statistical analysis on selected studies, Performing pooled analyses where appropriate, Submitting the results to technical experts for peer review, Incorporating reviewers comments into a final report for submission to AHRQ. Original Proposed Key Questions Preliminary questions for the project were developed by ODS in collaboration with the following NIH Institutes: (a) National Cancer Institute (NCI); (b) National Eye Institute (NEI); (c) National Heart, Lung, and Blood Institute (NHLBI); (d) National Institute of Alcohol Abuse and Alcoholism (NIAAA); (e) National Institute of Allergy and Infectious Diseases (NIAID); (f) National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS); (g) National Institute of Child Health and Human Development (NICHD); (h) National Institute of Diabetes Note: Appendixes and Evidence Tables cited in this report are provided electronically at 11

28 and Digestive and Kidney Diseases (NIDDK); (i) National Institute of Mental Health; and (j) National Institute of Neurological Disorders and Stroke (NINDS). The general and disease-specific questions that were originally proposed are detailed in Appendix A.1, Methodologic Approach. Technical Expert Panel Each AHRQ evidence report is guided by a Technical Expert Panel (TEP). The TEP advises the SCEPC on refining the preliminary questions, determining the proper inclusion/exclusion criteria for the study and the populations of interest, establishing the proper outcomes measures, and conducting the appropriate analyses. We convened three TEPs that focused on the following conditions: 1) rheumatoid arthritis (RA), systemic lupus erythematosis (SLE), and bone density/osteoporosis; 2) renal disease and diabetes; and 3) gastrointestinal (GI) diseases. The TEPs were composed of distinguished basic scientists and clinicians, with established expertise in the following areas: omega-3 fatty acids, human nutrition, dietary assessment methods, gastroenterology, nephrology, diabetes, osteoporosis, immunology, and rheumatology. In addition to the experts that we identified, AHRQ and the relevant NIH Institute(s) recommended a number of industry experts. The members of our technical expert panels and a summary of their key comments and recommendations are listed in Appendix A.2. Key Questions Addressed in this Report Based on input from our three TEPs, the preliminary disease-specific questions were revised. Additionally, in consultation with the Task Order Officer and the other participating EPCs, we added several questions to our scope of work that had previously been assigned to the NEMC/EPC because they were related to topics we were reviewing. Similarly, a question that had been assigned to the SCEPC for year two was reassigned to the NEMC-EPC. Lastly, one additional question (pertaining to rheumatoid arthritis number of tender joints) was suggested by a TEP member after reviewing the draft report and was assessed post-hoc. The questions that are addressed in this report are as follows: Diabetes What is the evidence in adults or children with a) type II diabetes, or b) insulin resistance/the metabolic syndrome for the efficacy of omega-3 fatty acids in treatment of: total cholesterol HDL cholesterol LDL cholesterol 12

29 Triglycerides What is the evidence in adults and children for an effect of omega-3 fatty acids on insulin sensitivity in a) type II diabetes, or b) the metabolic syndrome? Inflammatory Bowel Disease What is the evidence for the efficacy of omega-3 fatty acids in treatment of Crohn s disease and ulcerative colitis? What is the evidence that in adults or children with inflammatory bowel disease, omega-3 fatty acids can replace steroids or other immunosuppressive drugs? What is the evidence that the benefits of omega-3 fatty acids are influenced by the concomitant administration of various immunosuppressive agents in the treatment of inflammatory bowel disease? Rheumatoid Arthritis What is the evidence that in adults or children with rheumatoid arthritis, omega-3 fatty acids affect: pain number of swollen joints disease activity patient s global assessment joint damage number of tender joints What is the evidence that in adults or children with rheumatoid arthritis, omega-3 fatty acids can replace other more potent anti-inflammatory or immunosuppressive drugs such as steroids and NSAIDs? What is the evidence that the benefits of omega-3 fatty acids are influenced by the concomitant administration of various immunosuppressive agents in the treatment of rheumatoid arthritis? 13

30 Renal Disease What is the evidence for the efficacy of omega-3 fatty acids in treatment of renal inflammation and glomerulosclerosis? What is the evidence that in adults or children with immune-mediated renal disease, omega-3 fatty acids can replace steroids or other immunosuppressive drugs? What is the evidence that the benefits of omega-3 fatty acids are influenced by the concomitant administration of various immunosuppressive agents in the treatment of immune-mediated renal disease? Systemic Lupus Erythematosus What is the evidence that in adults or children with systemic lupus erythematosus, omega-3 fatty acids affect disease activity, damage, or patient perceptions of outcomes? What is the evidence that in adults or children with systemic lupus erythematosus, omega-3 fatty acids can replace steroids or other immunosuppressive drugs? What is the evidence that the benefits of omega-3 fatty acids are influenced by the concomitant administration of various immunosuppressive agents in the treatment of systemic lupus erythematosus? Bone Density/Osteoporosis What is the evidence that omega-3 fatty acids help maintain bone mineral status? For each of the study questions we also assessed 1) the effect of omega-3 fatty acids on subpopulations, 2) the effects of covariates, dose, source, and exposure duration on the outcomes of interest, and 3) the sustainment of effect. Assessment of Adverse Events In addition to assessing the efficacy of omega-3 fatty acids as specified above, we evaluated the data on adverse events that were reported in the studies we reviewed. We recognized, a priori, that adverse events are not reported in a standard way across clinical trials either in terms of the specific adverse events assessed or in the reporting of these adverse events. Hence, the purpose of this analysis was to define in general terms adverse events that occur with omega-3 fatty acids in order to identify specific adverse events that might warrant further investigation. From each study, we extracted the number of adverse events reported for both intervention and placebo groups. We grouped the adverse events into the following categories: Clinical bleeding Gastrointestinal complaints or nausea 14

31 Diarrhea Headache Dermatological Withdrawal due to adverse event We calculated rates of adverse events within the intervention and placebo groups. Adverse event rates were calculated as the percentage of patients pooled across all conditions who had one of the adverse events. Reporting of adverse events varied greatly across studies. Many studies did not report on adverse events. If a study did not report on an adverse event (i.e. missing value), it was not used in that adverse event calculation. If a study reported not having an adverse event (i.e. adverse event rate of 0%), it was used in the calculation. Studies that did not specify the group allocation of the adverse events were excluded. We also excluded studies that reported the number of adverse events but did not report the group sample sizes. Identification of Literature Sources Potential evidence for our study came from three sources: on-line library databases, the reference lists of all relevant articles, and industry experts. Jessie McGowan, Senior Information Scientist, and Nancy Santesso, Knowledge Translation Specialist, at the University of Ottawa were responsible for developing a common search strategy for omega-3 fatty acids for the 3 participating EPCs. Nancy Santesso developed a core omega-3 search strategy in collaboration with project librarians, biochemists, nutritionists, and clinicians, who also provided biochemical names, abbreviations, food sources, and commercial product names for omega-3 fatty acids. The literature search was not restricted by language of publication or by study design, except with the MeSH term, dietary fats, in order to increase specificity. When possible, the searches were limited to studies involving human subjects. The core search strategy is detailed in Appendix A.3. For the SCEPC, this core search strategy was incorporated into 6 specific searches that focused on our relevant disease categories: rheumatoid arthritis, bone density, SLE, renal disease, diabetes, and gastrointestinal diseases. The strategies for these searches are detailed in Appendix A.3. The following databases were searched: Medline (1966-July, 2003), Premedline (July 8, 2003), Embase (1980-Week 27, 2003), Cochrane Central Register of Controlled Trials (2nd Quarter, 2003), CAB Health (1973-June 2003), Dissertation Abstracts (1861-to December 2002). All of these databases were searched using the Ovid interface, except CAB Health, which was searched through SilverPlatter. Any duplicate records were identified and removed within each search question using Reference Manager software, except for the last update, which was imported into EndNote. The citations obtained from these literature searches were sent to the SCEPC via . The citations were transferred to a secured Internet-based software system (termed D2D) that enabled us to view article titles and abstracts electronically. Two reviewers, Walter Mojica and James Pencharz, used the computerized software system to independently evaluate the citations and abstracts using the review form in Figure B.1, Appendix B, which was loaded onto the computerized system. 15

32 The reviewers flagged article titles that focused on omega-3 fatty acids and any of the following disease conditions: diabetes mellitus, inflammatory bowel disease (ulcerative colitis and Crohn s disease), rheumatoid arthritis, SLE, renal disease, osteoporosis, or bone mineral status. In addition, they flagged article titles that pertained to the disease conditions of the other participating EPCs (i.e., cardiovascular disease or asthma). Language was not a barrier to inclusion. Articles that either reviewer flagged were ordered, as well as those articles in which it was unclear from the title or abstract whether the article was relevant. The articles were ordered from the RAND library, the UCLA library, or Kessler-Hancock, a San Francisco-based literature retrieval firm with contacts around the world. The literature was tracked using ProCite and Access software. In addition, we sent letters to industry experts recommended by the Office Dietary Supplements to obtain any unpublished data (Figure A.3.1). Evaluation of Evidence Two reviewers independently reviewed each article that was ordered to determine whether it should be accepted for further study using a structured screening form (shown in Figure B.2, Appendix B) that included a defined set of inclusive/exclusive criteria (Table A.4.1, Appendix A.4). Walter Mojica reviewed all of the articles; James Pencharz and Jennifer Grossman each reviewed a portion of the articles. The reviewers resolved any disagreements by consensus. Extraction of Data For the articles that passed our screening criteria, two reviewers independently abstracted detailed data onto a specialized quality review form (QRF) (Figure B.3, Appendix B). Walter Mojica and Jennifer Grossman reviewed all of the articles except those pertaining to diabetes, which were reviewed by Walter Mojica and Puja Khanna. We consulted with several outside scientists to complete QRFs for foreign-language articles. The reviewers resolved differences through consensus, and a senior physician researcher resolved any disagreements that could not be resolved through this method. The QRF included questions about the trial design; the outcomes of interest; the quality of the trial; the number and characteristics of the patients; details on the intervention, such as the dose, frequency, and duration; the types of outcome measures; adverse events; and the elapsed time between the intervention and outcome measurements. Grading Evidence Methodologic Quality of Randomized Controlled Trials To evaluate the quality of the design and execution of trials, we also collected information on the QRF about the study design, appropriateness of randomization, blinding, description of withdrawals and dropouts, and concealment of allocation. 6,113 A score for quality was calculated 16

33 for each trial using a system developed by Jadad (Appendix A.5, Figure A.5.1). The Jadad score rates studies on a scale of 0 to 5. Empirical evidence has shown that studies scoring 2 or less report exaggerated results compared with studies scoring 3 or more. 114,115 Thus, studies with a Jadad score of 3 or more are referred to as high quality, and studies scoring 2 or less are referred to as poor quality. For our purposes, if a trial was associated with more than one study, its quality score was equal to the maximum score calculated across its associated studies. Additionally, a generic summary quality score (A, B, C) was assigned to each study based upon the combination of its Jadad score and reporting of concealment of allocation (Appendix A.5, Table A.5.1). Applicability In this report, the focus is on the U.S. population. To capture the potential applicability of studies to the different populations of interest as defined in the scope of work (namely Americans with inflammatory bowel disease, rheumatoid arthritis, renal disease, systemic lupus erythematosus or osteoporosis), we categorized the populations in the studies we reviewed in terms of 1) applicability to the U.S. population and 2) health state (Appendix A.5, Table A.5.2). In the summary tables, each study receives a combined applicability grade consisting of the applicability and health state. Data Synthesis We performed both a qualitative and quantitative synthesis of the evidence. We performed a meta-analysis for those studies that sufficiently assessed interventions, populations, and outcomes to justify pooling. For the remaining studies, we performed a qualitative analysis. Meta-Analysis Our meta-analytic methods are sufficiently comparable across conditions and outcomes that we describe them in general in this section. Individual approaches and decisions are discussed as necessary and appropriate in the discussion of results for particular conditions and outcomes. Selection of Trials for Descriptive Analysis or Meta-Analysis For each condition, we identified a set of relevant outcomes, e.g., cholesterol outcomes for the condition of diabetes, based on input from our TEP. Trials were considered for further analysis if they contained information on a chosen outcome collected within a follow-up interval for which measures were considered clinically comparable. For some trials, several publications presented the same outcome data. In these cases, we picked the most informative of the duplicates; for example, if one publication was a conference abstract with preliminary data and the second was a full journal article, we chose the latter. The publications dropped for duplicate data do not appear in the evidence table but are noted in the 17

34 results text. We note that multiple citations of the same article were removed at the title screening stage of the project. In order for a trial to be included in further analysis, the associated publication(s) had to report on the outcome, and contain sufficient statistical information for the calculation of a summary statistic. A trial also had to provide data prior to the crossover point if the trial was a crossover design to mirror the data available from a non-crossover trial, i.e., to enable the inclusion of a treatment effect uncontaminated by other treatments. Had data been included after the cross-over, the uncontaminated placebo or control group outcome would not have been available for example. Trial Summary Statistics Each trial contained one control or placebo group. Some trials contained more than one treatment (omega-3) group. In order not to double-count patients, we chose the most clinically relevant treatment group to enter our analysis, or in some cases combined treatment groups. For those outcomes that were dichotomous, the summary statistic was a risk ratio, that is, the risk of the outcome in the treatment (omega-3) group divided by the risk of the outcome in the control or placebo group. A risk ratio greater than one indicates that the risk of the outcome in the treatment group is larger than that in the control or usual care arm. For example, if the risk ratio is 1.10, then patients in the treatment group are 1.10 times as likely to have the outcome as those in the control or placebo group. For each study, we estimated the log risk ratio and its standard deviation. We conducted the analysis on the logarithmic scale for variance-stabilization reasons. 7 We then back-transformed to the risk ratio scale for interpretability. For those outcomes that were continuous, we extracted the follow-up means and standard deviations for the treatment and control or placebo groups respectively. If a study did not report a follow-up mean, or a follow-up mean could not be calculated from the given data, the study was excluded from analysis. For studies that did not report a standard deviation or for which a standard deviation could not be calculated from the given data, we imputed the standard deviation by using those studies and groups that did report a standard deviation and weighting all groups equally, or we assumed that the standard deviation was 0.25 of the theoretical range for the specific measure in the study. For example, if a study measured pain on a scale, we assumed the standard deviation was 25. If all studies measured the outcome on the same scale or the measures could all be converted to the same scale, e.g., cholesterol measurements measured in mg/dl or mmol/l which could all be converted to mg/dl, the summary statistic was the mean difference (MD) between the treatment group follow-up mean and the control or placebo group follow-up mean: Mean difference = treatment follow-up mean control follow-up mean We estimated the standard deviation for that mean difference. 8 If the studies used different measurements of the same outcome and we could not convert them all to the same scale, the summary statistic was an effect size. The effect size is the mean difference at follow-up divided by the pooled standard deviation. This summary statistic is unitless and indicates the number of standard deviations by which the treatment and control or placebo group means differ. We estimated an unbiased estimate 9 of Hedges g effect size 10 and its standard deviation. A negative 18

35 mean difference or effect size indicates that the treatment is associated with a decrease in the outcome at follow-up as compared with the control or usual care group. Stratification of Trials For each condition, we performed, as permissible given available data, stratified analyses on subgroups of studies defined by patient population, type of omega-3, and dose of omega-3. We will discuss the particular strata definitions for each condition in the relevant results sections in Chapter 3. In general, a paucity of available data precluded us from pooling data separately in most strata. However, we do discuss the results qualitatively in each stratum when possible. Performance of Meta-Analysis In some cases, the trials were judged too clinically heterogeneous to combine. Furthermore, for each outcome, condition, and trial stratum combination, we required that at least three trials be available for pooling. In heterogeneous settings and those with insufficient data, we conduct only a descriptive analysis and present the study-level summary statistics but do not estimate a pooled effect. For those conditions for which trials were determined to be clinically comparable and for which there were at least three trials, we estimated a pooled random-effects estimate 11 by combining summary statistics across trials. We also report the chi-squared test of heterogeneity p-value. 9 Forest plots were constructed for each setting. Each individual trial summary statistic is shown as a box whose area is inversely proportional to the estimated variance of the summary statistic in that trial. The trial s confidence interval is shown as a horizontal line through the box. The pooled estimate and its confidence interval are shown as a diamond at the bottom of the plot with a dotted vertical line indicating the pooled estimate value. A vertical solid line at one for dichotomous outcomes or at zero for continuous outcomes indicates no treatment effect. Sensitivity Analyses We conducted post hoc sensitivity analysis for meta-analyses that exhibited significant (p<0.05) heterogeneity based on the chi-squared test of heterogeneity. In these sensitivity analyses, we removed the most outlying study chosen based on a visual inspection of the forest plot of the original meta-analysis, and estimated a new pooled estimate. We compared this pooled estimate to the original result as well as observed whether significant heterogeneity still remained. 19

36 Publication Bias We assessed the possibility of publication bias by evaluating a funnel plot of summary statistics for asymmetry, which can result from the nonpublication of small trials with negative results. These funnel plots include a horizontal line at the fixed-effects pooled estimate and pseudo 95% confidence limits. 9 If bias due to nonpublication exists, the distribution is asymmetric or skewed. Because graphical evaluation can be subjective, we also conducted an adjusted rank correlation test 10 and a regression asymmetry test 9 as formal statistical tests for publication bias. The correlation approach tests whether the correlation between the effect sizes and their variances is significant, and the regression approach tests whether the intercept of a regression of the effects sizes on their precision differs from zero; that is, both formally test for asymmetry in the funnel plot. We acknowledge that other factors, such as differences in trial quality or true study heterogeneity, could produce asymmetry in funnel plots. Interpretation of the Results The mean difference pooled results are readily interpretable as they are measured in a clinically interpretable metric. To aid in interpreting the pooled effect size and risk ratio, whenever possible we back-transformed each pooled estimate to a specific metric. In order to do this, we multiplied each pooled effect size estimate by the average standard deviation of the most clinically relevant outcome measured across the trials, e.g., pain on the VAS scale, included in the pooled estimate. For each pooled risk ratio, we estimated a number needed to treat (NNT) or number needed to harm (NNH) depending on whether the risk ratio was less than or greater to one, by assuming that the population outcome risk was equal to the average control group risk observed across the trials. By average in either calculation, we mean a simple average across relevant placebo/control and/or treatment groups in the relevant studies. We note these backtransformations require assuming a particular underlying standard deviation or outcome risk. Readers may wish to apply their own standard deviation or underlying risk, based on the particular patient population to which they wish to apply the results. We conducted all analyses and drew all graphs using the statistical package Stata. 11 Peer Review This draft report was sent for review to a select group of experts in omega-3 fatty acids, epidemiology, nutrition, rheumatoid arthritis, SLE, IBD, nephrology, osteoporosis, and diabetes. The names, expertise, and affiliations of the peer reviewers are listed in Table A.6.1, Appendix A. Additionally, the report was sent to the members of the TEP for review. We entered all comments that we received into a database and collated those pertaining to similar sections of the report. For each comment or group of related comments, we prepared a response detailing how we changed the report or why we did not believe a change was justified. The complete list of peer reviewed comments and our responses are included in Appendix D. Service as a peer reviewer or as a technical expert panelist does not imply agreement or endorsement of the findings of this report. 20

37 Chapter 3. Results Results of Literature Search Figure 3.1 displays the flow of the literature review. The University of Ottawa EPC ed us a total of 4,212 citations as a result of their computerized library searches. Our two reviewers considered 1,384 of these article titles to be relevant to our research topics. Of these, a senior researcher rejected 347 titles as not being relevant. We also received 25 citations from the literature searches conducted by New England Medical Center (NEMC) EPC, and we identified 42 articles by hand searching the reference lists of articles that we reviewed. Thus, we identified a total of 1,105 relevant article titles. We were able to retrieve all but 8 of these articles. Of the 1,097 articles retrieved, 115 were accepted for further review, because they reported on results from randomized clinical trials or controlled clinical trials of omega-3 fatty acids in the treatment of RA, IBD, diabetes, renal disease, and SLE or reported results from randomized clinical trials, controlled clinical trials, or case series of omega-3 fatty acids on the effects on bone mineral metabolism. Of those articles that were rejected at this stage, 149 reported on a condition other than those of interest, 301 reported on a topic other than omega-3 fatty acids, 22 did not report on a population of interest, and 504 were rejected for study design (i.e., descriptive studies or editorials/commentaries, previous reviews or meta-analyses, and observational studies in all topic areas except bone mineral metabolism). Three articles were duplicates of articles already on file, and four were not reviewed due to language. Of the 115 articles that went to further review, 10 were rejected because they did not report on outcomes of interest, 15 because they did not report a difference in omega-3 content among study arms, and 7 because they were duplicate reports of the same trial. Thus, a total of 83 articles were accepted for supplementary analysis. Of these, 21 articles reported on RA, 13 articles reported on IBD, 34 articles reported on diabetes, 9 articles reported on renal, 3 articles reported on lupus, and 4 articles reported on bone mineral metabolism. One article reported outcomes for both SLE and renal disease. Due to the limited number of articles found for renal failure, SLE, and bone mineral metabolism, these outcomes are discussed qualitatively. Ten trials were included in the meta-analysis of RA outcomes (not all trials were included for each outcome). Eleven trials were not included in meta-analysis for the following reasons: insufficient statistics and no outcome of interest. 38 Three trials were included in the meta-analysis of remission/relapse in ulcerative colitis. Ten trials were not included in meta-analysis for the following reasons: insufficient statistics, 42, 43,95 no outcome of interest, 44,46,52,53,94 54, 55 and wrong disease (Crohn s disease, not ulcerative colitis). Eighteen trials were included in the meta-analysis of diabetes outcomes (not all trials were included for each outcome). Sixteen articles were not included in meta-analysis for insufficient statistics ,86-91 In addition, as a result of our request to industry experts for unpublished data, Herbert Woolf, Technical Marketing Manager for BASF Corporation, sent us the following document: Food Labeling: Health Claims and Label Statement Omega-3 Fatty Acids and Coronary Heart Disease, prepared by members of the Joint Task Group (CHPA, CRN, NFI), FDA Docket No: 91N Note: Appendixes and Evidence Tables cited in this report are provided electronically at 21

38 Figure 3.1. Literature flow. Library Search: Titles Reviewed (n = 4,212) NEMC Screening (n = 25) Library Search (n = 1,384) Industry Request (n = 1) Reference Lists (n = 42) 347 Rejected on Abstract Review 1105 Articles Requested 8 Not Found 1097 Articles Screened 982 Rejected: 149 Condition 301 Topic 22 Population 29 Study Design: Descriptive 337 Study Design: Review/ Meta-analysis 138 Study Design: Not Appropriate 3 Duplicate article 3 Unable to find a translator 115 Articles Quality Reviewed 32 Rejected 15 No difference in Omega-3 content among arms 10 No criteria or outcomes of interest 7 Duplicate reports of same trial 83 Articles Included in Evidence Tables and Reviewed for Supplementary Analyses RA (n =21) Lupus* (n = 3) IBD (n =13 ) Bone (n = 4) Diabetes (n = 34) Renal* (n = 9) Qualitative Review Qualitative Review Qualitative Review RA 10 Trials included in MA Excluded articles: 10 for insufficient statistics 1 for no outcome of interest Crohn s disease 3 Trials included in MA Excluded articles: 3 for insufficient statistics 5 for no outcome of interest 2 for not disease of interest Diabetes 18 Trials included in MA Excluded articles: 16 for insufficient statistics * One article reported both lupus and renal outcomes. 22

39 DIABETES Summaries of all evaluated diabetes studies can be found in appendix C.1. Diabetes: Total Cholesterol Overall effect. We identified 32 studies 56-72, 75-83, that evaluated the effect to of omega- 3 fatty acids on total cholesterol in type II diabetics. Among these, 14 contained sufficient data to be included in a meta-analysis. (Table 3.1) The pooled random effects estimate of the mean difference between omega-3 fatty acids and placebo for total cholesterol is 0.72 mg/dl (95% CI, , 7.33) (Table 3.1 and Figure 3.2). Although a large number of the studies identified were not included in this meta-analysis, the results presented here are consistent with the results of another meta-analysis, 116 that included a number of the studies that were excluded here. Sub-populations. None of the studies evaluated the differential effects of omega-3 fatty acids on distinct subpopulations. There were insufficient data to perform pooled analyses on subpopulations across studies. Covariates. One study 58 assessed the effects of fish oil alone, atorvastatin alone, and combined fish oil and atorvastatin. Both atorvastatin alone and combined fish oil and atorvastatin reduced total cholesterol significantly, relative to placebo; there was an insignificant reduction with fish oil alone. The reduction for atorvastatin alone was greater than that for the other groups, although statistical testing was not reported. Effects of dose, source and exposure duration. None of the studies specifically assessed the effects of dose, source, or exposure duration. A pooled analysis of dose effect using meta-regression revealed no significant dose effect. On stratified analysis of source, the pooled random effects estimates of the mean difference between omega-3 fatty acids and placebo, for studies using a fish-oil and studies using a plant source, respectively, were 1.21 mg/dl (95% CI, , 8.49) and 1.82 (95% CI, -5.87, 12.20). Sustainment of effect. Sustainment of effect was not assessed in any of the reports. Quality and applicability. Among studies that entered the meta-analysis, none had both an applicability rating of I (representative of general adult population with type II diabetes), and a summary quality score of A (Jadad score = 5 with concealment of allocation) (Table 3.2). Similarly, there were no studies with the lowest rating of both applicability (III) and quality (C). Most studies were applicable to the general population of adult patients with type II diabetes. Of note, no studies were identified that assessed the effect of omega-3 fatty acids among children with type II diabetes. 23

40 Table 3.1. Diabetes: mean difference for total cholesterol. Intervention Control Mean Difference Trial Source n Source n (mg/dl) (95% CI) Alekseeva 65 Linseed oil 30 Placebo (-24.97, 29.60) Annuzzi 57 Max EPA (Fish oil) 4 Placebo (-21.65, 34.00) Chan 58 Omacor 12 Placebo (-36.35, 13.19) Omacor/Atorvastatin 11 Atorvastatin (-9.59, 32.76) Dunstan 59 Fish oil/light exercise 12 Placebo (-46.67, 8.06) Fish/moderate exercise 14 Placebo (-19.28, 34.73) Hendra 60 Max EPA (fish oil) 40 Placebo (-30.89, 7.72) Meshcheriakova 66 Linseed oil/eiconol 60 Low-fat/Low sodium diet (-15.75, 25.01) Morgan 61 Fish oil 10 Placebo 10 Fish oil 10 Placebo (-37.43, 11.18) Morgan 67 Low dosage Fish oil 7 Placebo (-96.98, 22.98) High dosage Fish oil 6 Placebo (-5.75, 53.75) Patti 68 Fish oil 8 Placebo (-57.98, 19.37) Pelikanova 62 Fish oil 10 Placebo (-12.96, 50.80) Petersen 63 Futura 1000 (fish oil) 20 Placebo (-5.97, 39.95) Sarkkinen 70 Rapeseed (LEAR) oil 17 Sunflower oil (-45.21, 9.69) Shimizu 56 EPA-E 29 Placebo (-2.30, 27.10) Woodman 72 EPA 17 DHA 18 Placebo (-22.48, 12.97) Pooled Random Effects Estimate* *Chi-squared test of heterogeneity p-value = (-5.90, 7.33) Table 3.2. Relationship between methodologic quality and applicability for estimates of effect of omega-3 fatty acid consumption on total cholesterol among people with type II diabetes. I Methodological Quality A B C Study n Mean difference Study n Mean difference (95% CI) (95% CI) Hendra (-30.89, 7.72) Shimizu (-2.30, 27.10) Morgan (-96.98, 22.98) (-5.75, 53.75) Morgan (-37.43, 11.18) Applicability II III Petersen (-5.97, 39.95) Patti (-57.98, 19.37) Chan (-36.35, 13.19) (-9.59, 32.76) Woodman (-22.48, 12.97) Dunstan 25 Sarkkinen (-45.21, 9.69) Annuzzi (-21.65, 34.00) (-46.67, 8.06) (-19.28, 34.73) Pelikanova (-12.96, 50.80) 24

41 Figure 3.2. Diabetes: total cholesterol. Annuzzi 57 Alekseeva 65 Chan 58 Chan 58 Dunstan 59 Dunstan 59 Hendra 60 Morgan 61 Meshcheriakova 66 Morgan 67 Morgan 67 Patti 68 Pelikanova 62 Petersen 63 Sarkkinen 70 Shimizu 56 Woodman 72 Combined -97 Favors 0.72 Favors 54 treatment control Mean difference 25

42 Diabetes: HDL Cholesterol Overall effect. We identified 30 studies 56-61, 63,64,67-73, 75-83, that evaluated the effect to of omega-3 fatty acids on HDL cholesterol in type II diabetics. Among these studies, 12 contained sufficient data to be included in a meta-analysis. (Table 3.4) The pooled random effects estimate of the mean difference between omega-3 fatty acids and placebo for HDL cholesterol is 1.17 mg/dl (95% CI, -1.08, 3.42) (Table 3.3 and Figure 3.3). Although a large number of the studies identified were not included in this meta-analysis, the results presented here are consistent with the results of another meta-analysis 116 studies evaluated the differential effects of omega-3 fatty acids on distinct subpopulations. There were insufficient data to perform pooled analyses on subpopulations across studies. Covariates. One study assessed the effects of fish oil alone, atorvastatin alone, and combined fish oil and atorvastatin. 58 There was an insignificant increase and decrease in HDL with atorvastatin alone and fish oil alone, respectively, and a significant increase with a combination of fish oil and atorvastatin. Effects of dose, source, and exposure duration. None of the studies specifically assessed the effects of dose, source or exposure duration. A pooled analysis of dose effect using meta-regression revealed no significant dose effect. In one study, plants were the source of omega-3 fatty acids. In this study, 70 the mean difference between omega-3 fatty acids and placebo for HDL cholesterol was 3.09 mg/dl (95% CI, -9.84, 3.67). Restricting the pooled analysis to the remaining studies, which used a fish source, the pooled random effects estimate of the mean difference between omega-3 fatty acids and placebo for HDL cholesterol was 1.53 mg/dl (95% CI, -0.82, 3.87). Sustainment of effect. Sustainment of effect was not assessed in any of the reports. Quality and applicability. Among studies that entered the meta-analysis, none had both an applicability rating of I (representative of general adult population with type II diabetes), and a summary quality score of A (Jadad score = 5 with concealment of allocation) (Table 3.4). Similarly, there were no studies with the lowest rating of both applicability (III) and quality (C). Most studies were applicable to the general population of adult patients with type II diabetes. Of note, no studies were identified that assessed the effect of omega-3 fatty acids among children with type II diabetes. 26

43 Table 3.3. Diabetes: mean difference for high-density lipoprotein (HDL). Intervention Control Mean Difference Trial Source n Source n (mg/dl) (95% CI) Annuzzi 57 Max EPA (Fish oil) 4 Placebo (-3.21, 3.21) Chan 58 Omacor 12 Placebo (-6.33, 4.78) Omacor/Atorvastatin 11 Atorvastatin (0.63, 15.59) Dunstan 59 Fish oil/light exercise 12 Placebo (-3.90, 13.16) Fish oil/mod. exercise 14 Placebo (-8.03, 8.80) Hendra 60 Max EPA (fish oil) 40 Placebo (-14.68, -0.76) Morgan 61 Fish oil 10 Placebo 10 Fish oil 10 Placebo (-6.18, 11.58) Maffettone 73 Fish oil 8 Placebo (-10.69, 6.06) Morgan 67 Low dosage Fish oil 7 Placebo (-3.49, 21.49) High dosage Fish oil 6 Placebo (-13.03, 31.03) Patti 68 Fish oil 8 Placebo (-10.78, 6.14) Petersen 63 Futura 1000 (fish oil) 20 Placebo (0.13, 13.00) Sarkkinen 70 Rapeseed (LEAR) oil 17 Sunflower oil (-9.84, 3.67) Shimizu 56 EPA-E 29 Placebo (-2.70, 14.30) Woodman 72 EPA 17 DHA 18 Placebo (-4.44, 8.48) Pooled Random Effects Estimate* *Chi-squared test of heterogeneity p-value = (-1.08, 3.42) Table 3.4. Relationship between methodologic quality and applicability for estimates of effect of omega-3 fatty acid consumption on HDL among people with type II diabetes. Applicability I II III Methodological Quality A B C Study n Mean difference (95% CI) Study n Mean difference (95% CI) Hendra (-14.68, -0.76) Shimizu (-2.70, 14.30) Morgan (-3.49, 21.49) Morgan (-6.18, 11.58) (-13.03, 31.03) Petersen (0.13, 13.00) Patti (-10.78, 6.14) Chan (-6.33, 4.78) (0.63, 15.59) Woodman (-4.44, 8.48) Sarkkinen (-9.84, 3.67) Annuzzi (-3.21, 3.21) Dunstan (-3.90, 13.16) (-8.03, 8.80) 27

44 Figure 3.3. Diabetes: high density lipoprotein (HDL). Annuzzi 57 Chan 58 Chan 58 Dunstan 59 Dunstan 59 Hendra 60 Morgan 61 Maffettone 73 Morgan 67 Morgan 67 Patti 68 Petersen 63 Sarkkinen 70 Shimizu 56 Woodman 72 Combined Favors Favors control treatment Mean difference 28

45 Diabetes: LDL Cholesterol Overall effect. We identified 28 studies that evaluated the effect of omega-3 fatty acids on LDL cholesterol in type II diabetics 57-61, 63,64,67, 69-73, 75-83, Among these, 11 contained sufficient data to be included in a meta-analysis. (Table 3.5) The pooled random effects estimate of the effect of omega-3 fatty acids on LDL cholesterol is 5.12 mg/dl (95% CI, -1.02, 11.25) (Table 3.5 and Figure 3.4). Although a large number of the studies identified were not included in this meta-analysis, the results presented here are consistent with the results of another metaanalysis, 116 that included a number of the studies that were excluded here, although the results in the other meta-analysis were statistically significant. Sub-populations. None of the studies evaluated the differential effects of omega-3 fatty acids on distinct subpopulations. There were insufficient data to perform pooled analyses on subpopulations across studies. Covariates. One study 58 assessed the effects of fish oil alone, atorvastatin alone, and a combination of fish oil and atorvastatin. Atorvastatin alone and combined fish oil and atorvastatin reduced LDL cholesterol with significantly relative to placebo; fish oil alone reduced LDL cholesterol relative to placebo, though not significantly. The reduction was greatest for atorvastatin alone, although statistical testing between atorvastatin and fish oil groups was not reported. Effects of dose, source and exposure duration. None of the studies specifically assessed the effects of dose, source or exposure duration. A pooled analysis of dose effect using meta-regression revealed no significant dose effect. In one study, plants were the source of omega-3 fatty acids. In this study, 70 the mean difference between omega-3 fatty acids and placebo for LDL cholesterol was mg/dl (95% CI, , 17.30). Restricting the pooled analysis to the remaining studies, which used a fish source, the pooled random effects estimate of the mean difference between omega-3 fatty acids and placebo for LDL cholesterol was 5.92 mg/dl (95% CI, -0.38, 12.22). Sustainment of effect. Sustainment of effect was not assessed in any of the reports. Quality and applicability. Among studies that entered the meta-analysis, none had both an applicability rating of I (representative of general adult population with type II diabetes) and a summary quality score of A (Jadad score = 5 with concealment of allocation) (Table 3.6). Similarly, there were no studies with the lowest rating of both applicability (III) and quality (C). Most studies were applicable to the general population of adult patients with type II diabetes. Of note, no studies were identified that assessed the effect of omega-3 fatty acids among children with type II diabetes. 29

46 Table 3.5. Diabetes: mean difference for low-density lipoprotein (LDL). Intervention Control Mean Difference Trial Source n Source n (mg/dl) (95% CI) Annuzzi 57 Max EPA (Fish oil) 4 Placebo (-9.22, 55.56) Chan 58 Omacor 12 Placebo (-20.88, 9.29) Omacor/Atorvastatin 11 Atorvastatin (-4.51, 28.45) Dunstan 59 Fish oil/light exercise 12 Placebo (-21.44, 31.48) Fish oil/mod. exercise 14 Placebo (-6.81, 45.42) Hendra 60 Max EPA (fish oil) 40 Placebo (-22.97, 15.25) Morgan 61 Fish oil 10 Placebo 10 Fish oil 10 Placebo (-19.46, 35.67) Maffettone 73 Fish oil 8 Placebo (-47.32, 46.55) Morgan 67 Low dosage Fish oil 7 Placebo (-52.53, 68.53) High dosage Fish oil 6 Placebo (-31.39, 77.39) Petersen 63 Futura 1000 (fish oil) 20 Placebo (2.79, 40.45) Rivellese 69 Fish oil 8 Placebo (-47.31, 46.54) Sarkkinen 70 Rapeseed (LEAR) oil 17 Sunflower oil (-37.38, 17.30) Woodman 72 EPA 17 DHA 18 Placebo (-13.80, 14.79) Pooled Random Effects Estimate* *Chi-squared test of heterogeneity p-value = (-1.02, 11.25) Table 3.6. Relationship between methodologic quality and applicability for estimates of effect of omega-3 fatty acid consumption on LDL among people with type II diabetes. Methodological Quality A B C I Study n Mean difference (95% CI) Study n Mean difference (95% CI) Hendra (-22.97, 15.25) Morgan (-19.46, 35.67) Applicability II Morgan (-52.53, 68.53) (-31.39, 77.39) Rivallese (-47.31, 46.54) Petersen (2.79, 40.45) Sarkkinen (-37.38, 17.30) Chan (-20.88, 9.29) Annuzzi (-9.22, 55.56) (-4.51, 28.45) Woodman (-13.80, 14.79) Dunstan (-21.44, 31.48) (-6.81, 45.42) III 30

47 Figure 3.4. Diabetes: low density lipoprotein (LDL). Annuzzi 57 Chan 58 Chan 58 Dunstan 59 Dunstan 59 Hendra 60 Morgan 61 Maffettone 73 Morgan 67 Morgan 67 Petersen 63 Rivellese 69 Sarkkinen 70 Woodman 72 Combined -52 Favors Favors treatment control Mean difference 31

48 Diabetes: Triglycerides Overall effect. We identified 33 studies that evaluated the effect to of omega-3 fatty acids on triglycerides in type II diabetics , 74-83, Among these, 14 contained sufficient data to be included in a meta-analysis. (Table 3.7) The pooled random effects estimate of the mean difference between omega-3 fatty acids and placebo for triglycerides is mg/dl (95% CI, , ) (Table 3.7 and Figure 3.5). Although a large number of the studies identified were not included in this meta-analysis, the results presented here are consistent with the results of another meta-analysis, 116 that included a number of the studies that were excluded here. Sub-populations. None of the studies evaluated the differential effects of omega-3 fatty acids on distinct subpopulations. There were insufficient data to perform pooled analyses on subpopulations across studies. Covariates. One study 58 assessed the effects of fish oil alone, atorvastatin alone and combined fish oil and atorvastatin. Fish oil alone, atorvastatin alone and combined fish oil and atorvastatin reduced triglycerides significantly relative to placebo. The reduction for combined atorvastatin and fish oil was greater that for either drug alone, although statistical testing was not reported. One study assessed the independent and combined effects of aerobic exercise and dietary fish intake on serum lipids and glycemic control. 93 There was a significant reduction in triglycerides and an increase in glycosylated hemoglobin with a diet high in fish. With combined moderate exercise and the fish diet, reduction in triglycerides was maintained and glycosylated hemoglobin did not increase. Effects of dose, source, and exposure duration. None of the studies specifically assessed the effects of dose, source, or exposure duration. A pooled analysis of dose effect using meta-regression revealed no significant dose effect. On stratified analysis of source, the pooled random effects estimates of the mean difference between omega-3 fatty acids and placebo, for studies using a fish-oil and studies using a plant source, respectively, were mg/dl (95% CI, , ) and (95% CI, , 32.73). Sustainment of effect. Sustainment of effect was not assessed in any of the reports. Quality and applicability. Among studies that were included in the meta-analysis, none had both an applicability rating of I (representative of general adult population with type II diabetes), and a summary quality score of A (Jadad score = 5 with concealment of allocation) (Table 3.8). Similarly, there were no studies with the lowest rating of both applicability (III) and quality (C). Most studies were applicable to the general population of adult patients with type II diabetes. Of note, no studies that assessed the effect of omega-3 fatty acids among children with type II diabetes were identified. 32

49 Table 3.7. Diabetes: mean difference for triglycerides. Intervention Control Mean Difference Trial Source n Source n (mg/dl) (95% CI) Annuzzi 57 Max EPA (Fish oil) 4 Placebo (-84.25, 18.77) Alekseeva 65 Linseed oil 30 Placebo (-33.54, ) Chan 58 Omacor 12 Placebo ( , ) Omacor/Atorvastatin 11 Atorvastatin (-52.99, 17.59) Fish oil/light exercise 12 Placebo ( , ) Dunstan 59 Fish oil/moderate exercise 14 Placebo ( , 26.65) Hendra 60 Max EPA (fish oil) 40 Placebo (-89.80, 1.31) Meshcheriakova 66 Low-fat/Low 60 Linseed oil/eiconol sodium diet (-88.83, 18.03) Morgan 61 Fish oil 10 Placebo 10 Fish oil 10 Placebo ( , ) Morgan 67 Low dosage Fish oil 7 Placebo ( , 35.44) High dosage Fish oil 6 Placebo ( , 96.19) Patti 68 Fish oil 8 Placebo (-89.24, 50.30) Pelikanova 62 Fish oil 10 Placebo ( , 29.33) Petersen 63 Futura 1000 (fish oil) 20 Placebo ( , 14.63) Sarkkinen 70 Rapeseed (LEAR) oil 17 Sunflower oil (-80.05, 34.03) Shimizu 56 EPA-E 29 Placebo (-23.37, 84.17) Woodman 72 EPA 17 DHA 18 Placebo (-68.98, ) Pooled Random Effects Estimate* *Chi-squared test of heterogeneity p-value = (-49.58, ) Table 3.8. Relationship between methodologic quality and applicability for estimates of effect of omega-3 fatty acid consumption on triglycerides among people with type II diabetes. I Methodological Quality A B C Study n Mean difference (95% CI) Study n Mean difference (95% CI) Hendra (-89.80, 1.31) Shimizu (-23.37, 84.17) Applicability II III Morgan ( , 35.44) ( , 96.19) Morgan ( , ) Petersen ( , 14.63) Patti (-89.24, 50.30) Sarkkinen (-80.05, 34.03) Chan ( , ) Annuzzi (-84.25, 18.77) (-42.99, 17.59) Woodman (-68.98, ) Dunstan ( , ) ( , 26.65) Pelikanova ( , 29.33) 33

50 Figure 3.5. Diabetes: triglycerides. Annuzzi 57 Alekseeva 65 Chan 58 Chan 58 Dunstan 59 Dunstan 59 Hendra 60 Morgan 61 Meshcheriakova 66 Morgan 67 Morgan 67 Patti 68 Pelikanova 62 Petersen 63 Sarkkinen 70 Shimizu 56 Woodman 72 Combined -660 Favors treatment Mean difference Favors control 34

51 Diabetes: Insulin Sensitivity/Glycemic Control Overall effect. We identified 3 studies that evaluated the effect to of omega-3 fatty acids on plasma insulin in type II diabetics, 57, 82, 93 and 1 that evaluated this effect in the metabolic syndrome. 92 We did not perform meta-analysis because the outcomes used for measuring plasma insulin in these studies were sufficiently different to preclude pooling across studies. In one study among type II diabetics, glucose-stimulated plasma insulin response during a hyperglycemic clamp was not influenced by fish oil. 57 In the second study, there was no effect on fasting serum insulin or insulin as measured by area under the curve during a fasting glucose tolerance test. 93 In the third study, there was no difference in insulin suppression of hepatic glucose production or in insulin stimulation of whole-body glucose disposal measured by the euglycemic-hyperinsulinemic clamp. 82 In the study of metabolic syndrome, fish oil had no effect on insulin resistance estimated by Homeostatic Model Assessment. 92 We identified 26 studies that evaluated the effect of omega-3 fatty acids on fasting blood sugar in type II diabetics. 57, 59-61, 63-65,67-72, 75-83,86,87, Among these, 9 contained sufficient data to be included in a meta-analysis. (Table 3.9) The pooled random effects estimate of the mean difference between omega-3 fatty acids and placebo for fasting blood sugar is 5.87 mg/dl (95% CI, -0.15, 11.88) (Table 3.9 and Figure 3.6). Although a large number of the studies identified with this outcome were not included in this meta-analysis, the results presented here are consistent with the results of another meta-analysis, 116 that included a number of the studies that were excluded here. We identified 23 studies that evaluated the effect of omega-3 fatty acids on glycosylated hemoglobin in type II diabetics. 56,57, 61-64, 67-69, 71,72,74-76, 78,79, 80-83, 86,87,90,91 Among these 8 contained sufficient data to be included in a meta-analysis. (Table 3.11) The pooled random effects estimate of the mean difference between omega-3 fatty acids and placebo for glycosylated hemoglobin is 0.21 (%) (95% CI, -0.01, 0.44) (Table 3.11 and Figure 3.12). Although a large number of the studies identified with this outcome were not included in this meta-analysis, the results presented here are consistent with the results of another metaanalysis, 116 that included a number of the studies that were excluded here. Sub-populations. The effects of omega-3 fatty acids on insulin were assessed in type II diabetes and metabolic syndrome. Covariates. One study assessed the effects of fish oil alone, atorvastatin alone and combined fish oil and atorvastatin. 92 There were increases in HOMA scores with fish oil alone, atorvastatin alone and combined fish oil and atorvastatin relative to placebo, though none were significant. Statistical testing was not reported, except the comparisons with placebo. One study assessed the independent and combined effects of aerobic exercise and dietary fish intake on serum lipids and glycemic control. 93 There was a significant reduction in triglycerides and an increase in glycosylated hemoglobin with fish diet. With a combination of moderate exercise and fish diet, reduction in triglycerides was maintained and glycosylated hemoglobin did not increase. 35

52 Effects of dose, source, and exposure duration. None of the studies specifically assessed the effects of dose, source, or exposure duration. A pooled analysis of dose effect using meta-regression revealed no significant dose effect on fasting blood glucose or glycosylated hemoglobin. No studies were identified that assessed the effects of omega-3 fatty acids from a plant source on insulin sensitivity or glycemic control. Sustainment of effect. Sustainment of effect was not assessed in any of the reports. Quality and applicability. Among studies that were included in the meta-analysis for fasting blood glucose and glycosylated hemoglobin, none had both an applicability rating of I (representative of general adult population with type II diabetes), and a summary quality score of A (Jadad score = 5 with concealment of allocation) (Tables 3.10 and 3.12). Similarly, there were no studies with the lowest rating of both applicability (III) and quality (C). Most studies were applicable to the general population of adult patients with type II diabetes. Of note, no studies that assessed the effect of omega-3 fatty acids among children with type II diabetes were identified. Table 3.9. Diabetes: mean difference of fasting blood glucose. Intervention Control Mean Difference Trial Source n Source n (mg/dl) (95% CI) Annuzzi 57 Max EPA (Fish oil) 4 Placebo (-66.18, 50.32) Alekseeva 65 Linseed oil 30 Placebo (-24.30, 42.32) Dunstan 59 Fish oil/light exercise 12 Placebo (-33.00, 51.02) Fish oil/mod. exercise 14 Placebo (-37.85, 45.06) Hendra 60 Max EPA (fish oil) 40 Placebo (-18.06, 61.3) Morgan 61 Fish oil 10 Placebo 10 Fish oil 10 Placebo (-52.95, 24.12) Morgan 67 Low dosage Fish oil 7 Placebo ( , 32.16) High dosage Fish oil 6 Placebo (-89.43, 55.43) Patti 68 Fish oil 8 Placebo (-28.67, 50.29) Sirtori 64 Esepent (fish oil) 203 Placebo (-2.82, 11.42) Woodman 72 EPA 17 DHA 18 Placebo (2.25, 37.37) Pooled Random Effects Estimate* *Chi-squared test of heterogeneity p-value = (-0.15, 11.88) 36

53 Table Relationship between methodologic quality and applicability for estimates of effect of omega-3 fatty acid consumption on fasting blood sugar among people with type II diabetes. Applicability I II III Methodological Quality A B C Study n Mean difference (95% CI) Study n Mean difference (95% CI) Hendra (-18.06, 61.30) Morgan (-52.95, 24.12) 67 Morgan ( , 32.16) (-89.43, 55.43) Sirtori (-2.82, 11.42) Patti (-28.67, 50.29) Woodman (2.25, 37.37) Annuzzi (-66.18, 50.32) Dunstan (-33.00, 51.02) (-37.85, 45.06) Figure 3.6. Diabetes: fasting blood glucose. Annuzzi 57 Alekseeva 65 Dunstan 59 Dunstan 59 Hendra 60 Morgan 61 Morgan 67 Morgan 67 Patti 68 Sirtori 64 Woodman 72 Combined -114 Favors Favors control 61 treatment Mean difference 37

54 Table Diabetes: effect size of hemoglobin A1c (HbA1c). Intervention Control Trial Source n Source n (%) (95% CI) Morgan 61 Fish oil 10 Placebo 10 Fish oil 10 Placebo (-1.25, 1.05) Morgan 67 Low dosage Fish oil 7 Placebo (-3.42, 0.82) High dosage Fish oil 6 Placebo (-0.68, 2.08) Patti 68 Fish oil 8 Placebo (-0.79, 1.99) Pelikanova 62 Fish oil 10 Placebo (0.02, 1.78) Shimizu 56 EPA-E 29 Placebo (-8.44, 8.56) Sirtori 64 Esepent (fish oil) 203 Placebo (-0.12, 0.46) Westerveld 71 EPA-E 8 EPA-E 8 Placebo (-3.55, 0.95) EPA 17 Woodman 72 DHA 18 Pooled Random Effects Estimate* *Chi-squared test of heterogeneity p-value = 0.52 Placebo (-0.28, 0.75) 0.21 (-0.01, 0.44) Table Relationship between methodologic quality and applicability for estimates of effect of omega-3 fatty acid consumption on glycosylated hemoglobin among people with type II diabetes. Applicability I Methodological Quality A B C Study n Mean difference (95% CI) Study n Mean difference (95% CI) Morgan (-3.42, 0.82) Morgan (-1.25, 1.05) (-0.68, 2.08) Sirtori (-0.12, 0.46) Patti (-0.79, 1.99) Westerveld (-3.55, 0.95) II Woodman (-0.28, 0.75) Pelikanova (0.02, 1.78) III 38

55 Figure 3.7. Diabetes: hemoglobin A1 c (HgA1 c). Morgan 61 Morgan 67 Morgan 67 Patti 68 Pelikanova 62 Shimizu 56 Sirtori 64 Westerveld 71 Woodman 72 Combined -8.5 Favors 0.21 Favors control 8.5 treatment Mean difference 39

56 INFLAMMATORY BOWEL DISEASE Summaries of all inflammatory bowel disease studies that were evaluated can be found in appendix C.2. Inflammatory Bowel Disease: Clinical Effect Overall effect. The effect of omega-3 fatty acids on each of the following outcomes was assessed: clinical score, sigmoidoscopic score, histologic score, induced remission and relapse. In total, 13 studies described in 14 reports were identified that reported these outcomes. All outcomes were assessed separately for ulcerative colitis and Crohn s disease. There were sufficient data to perform meta-analysis only for relapse and only for ulcerative colitis. Clinical score was described for ulcerative colitis in 5 studies; two reported no effect 39, 52 and three 44, 46, 94 reported statistically significant improvement with omega-3 fatty acids. Clinical score was described for Crohn s disease in only 1 study, which reported no effect. 52 Sigmoidoscopic score was reported for ulcerative colitis in 3 studies, 44, 52, 94 each of which reported a statistically significant improvement with omega-3 fatty acids. Sigmoidoscopic score was reported for Crohn s disease in 1 study, 52 which showed a statistically significant improvement with omega-3 fatty acids. Histologic score was reported for ulcerative colitis in 3 studies; 2 reported no effect 42, 46 and 1 statistically significant improvement. 44 Histologic score was not reported in any of the studies of Crohn s disease. Induction of remission was reported for ulcerative colitis in 2 studies, 44, 95 both of which showed improvement with omega-3 fatty acids. However, neither was statistically significant, and in one study, 44 comparable data for the placebo group was not reported. Induction of remission was not reported in the studies of Crohn s disease. Relapse was described for ulcerative colitis in 5 studies, 3 of which could be used for metaanalysis. Among these studies, 1 reported a lower relapse rate with omega-3 fatty acids than with placebo, 42 2 found no difference and 2 reported an increased rate of relapse. 39, 43 However, the results were not statistically significant in any of these studies. The pooled random effect estimate of the risk of relapse for omega-3 fatty acids relative to placebo for ulcerative colitis was 1.13 (95% CI: 0.81, 1.57) (Table 3.13, Figure 3.7). The data yield an average control group risk of 38% (all studies weighted equally). Combining these yields a NNH of 21. So the number of patients needed to treat on average to result in one relapse is 21. Among the studies not included in the meta-analysis, one reported a lower relapse rate and one reported a higher relapse rate with omega-3 fatty acids. Relapse was described for Crohn s disease in two studies; one reported a significantly lower relapse rate with omega-3 fatty acids than with placebo. 54 Sub-populations. Among the 13 studies identified, the study sample was restricted to patients with ulcerative colitis in , 46, 53, 94, 95 and to Crohn s disease in two; 54, 55 one study included both patients with ulcerative colitis and those with Crohn s disease and reported data separately for each disease. 52 In this study, the effect of omega-3 fatty acids on clinical score was the same for subjects with ulcerative colitis and Crohn s disease (no effect). The effect on histologic score was also the same; however the improvement reached statistical significance only when diseases were pooled. 40

57 Covariates. Reported covariates included use of other drugs, previous surgery and presence of fistulae. However, no comparisons of the effects of covariates on outcomes were identified. Effects of dose, source, and exposure duration. All studies identified used fish oil as the source of omega-3 fatty acids. No studies compared the effect of different doses of omega-3 fatty acids. There were too few studies that assessed the effects of any single outcome to perform a pooled analysis of dose effect. Of note, one study administered the fish oil via an enteric-coated capsule, which was designed to deliver the omega-3 fatty acids to the small bowel. 54 This study, which included only patients with Crohn s disease, demonstrated a reduced relapse rate relative to placebo. Duration of exposure varied from 2 to 24 months across the studies. Too few studies assessed any single outcome across similar time periods to analyze the effect of duration of exposure. Sustainment of effect. Sustainment of the assessed effects was not evaluated in any of the studies. Quality and applicability. Among studies that entered the meta-analysis, none had both an applicability rating of I (representative of general population with IBD) and a summary quality score of A (Jadad score = 5 with concealment of allocation). Similarly, there were no studies with the lowest rating of both applicability (III) and quality (C). Most studies were applicable to the general population of adult patients with IBD. Of note, no studies that assessed the effect of omega-3 fatty acids among children with IBD were identified. Table Ulcerative colitis disease: relative risk of relapse. Intervention Control Trial Source n Source n Relative Risk (95% CI) Hawthorne 41 Hi EPA 35 Placebo (0.71, 2.46) Loeschke 39 Fish oil 31 Placebo (0.69, 1.64) Mantzaris 40 Max EPA (fish oil) 22 Placebo (0.36, 2.70) Pooled Random Effects 1.13 (0.81, 1.57) Estimate* *Chi-squared test of heterogeneity p-value =

58 Table Relationship between methodological quality and applicability for estimates of effect of omega-3 fatty acid consumption with ulcerative colitis disease for relapse/remission. I Methodological Quality A B C Study n Relative Risk (95%, CI) Loeschke (0.69, 1.64) Mantzaris (0.36, 2.70) Applicability II III Hawthorne (0.71, 2.46) Figure 3.8. Ulcerative colitis disease: relative risk of relapse. Hawthorne 41 Loeschke 39 Mantzaris 40 Combined Relative Risk 42

59 Inflammatory Bowel Disease: Effect on Requirement for Steroids/Other Immunosuppressive Drugs Overall effect. We identified only 2 studies that assessed the effect of omega-3 fatty acids on requirements for corticosteroids or other immunosuppressive agents, both of which assessed the effect on corticosteroid requirement. 44, 53 Both of these studies found a reduced requirement for corticosteroids with omega-3 fatty acid treatment relative to placebo, but the differences were not statistically significant. Sustainment of effect after discontinuation of the omega-3 fatty acids was not assessed. We found no data on the effect of omega-3 fatty acids on requirements for steroids and other immunosuppressive drugs for different subpopulations, doses, exposures and sources. RHEUMATOID ARTHRITIS Summaries of all rheumatoid arthritis studies we evaluated can be found in Appendix C.3. Rheumatoid Arthritis: Pain Overall effect. The effect of omega-3 fatty acids on patient-assessed pain in rheumatoid arthritis was described in 19 studies, 9 of which could be used for meta-analysis. Among these studies, 3 reported significant improvement relative to placebo, 17, 29, 34 and 4 reported significant 18, 19, 22- improvement from baseline. 16, 21, 26, 30 There were no significant effects in twelve studies. 25, 28, 31-33, 35, 38 The pooled random estimate of effect size for the effect of omega-3 fatty acids on pain relative to placebo is (95% CI, -0.43, 0.06) (Table 3.15, Figure 3.8). An effect size of 1.0 is equivalent to 2.72 cm units on the Visual Analogue Scale. Hence, an effect size of translates to a 0.52 cm decrease on the visual analog scale. Of note, among the 10 studies that were not included in the meta-analysis, 8 did not demonstrate a significant effect from omega-3 29, 34 fatty acids, and 2 did demonstrate such an effect. Sub-populations. None of the studies assessed the effects of omega-3 fatty acids on different subpopulations of patients with RA. Covariates. One study assessed the effect of different diets (Western versus modified lactovegetarian) combined with omega-3 fatty acids on pain in RA. 26 In this study, among subjects treated with fish oil, there was a reduction in pain among patients on a modified lacto-vegetarian diet relative to a Western diet (P<0.01) Effects of dose, source, and exposure duration. One study assessed the effect of different doses of omega-3 fatty acids on outcomes in RA. 19 In this study, the effect of fish oil on pain did not differ among doses. There were insufficient data across studies to perform a pooled analysis of dose or source effect. In 1 study, plants were the source of omega-3 fatty acids. In this study 23 the effect size for omega-3 fatty acids for pain was (95% CI, -1.04, 0.63). Restricting the pooled analysis to 43

60 the remaining studies, which used a fish source, the pooled random effects estimate of the effect size for pain is unchanged at 0.19 (95% CI, -0.46, 0.09). Only 1 study assessed the effects of different durations of exposure on outcomes in RA. 19 In this study, there was no effect on pain at 24 and 36 weeks, although statistical testing of the effect between these time points was not performed. There were insufficient data across studies to perform a pooled analysis of exposure duration effect. Sustainment of effect. Two studies assessed the sustainment of effects of omega-3 fatty 18, 28 acids on outcomes in RA. In 1 study, pain worsened in a fish oil-treated arm 3 months after discontinuation of the fish oil (p<0.05). In the other study, 100% of the control arm (evening primrose oil) and 80% of the fish oil group returned to baseline or became worse. Although pain, joint swelling, and acute phase reactants were assessed in this study, the parameters on which this assessment was made were not specified. There were insufficient data across studies to perform a pooled analysis of sustainment of effect. Quality and applicability. Among studies that entered the meta-analysis, none had both an applicability rating of I (representative of general adult population with rheumatoid arthritis), and a summary quality score of A (Jadad score = 5 with concealment of allocation) (Table 3.16). Similarly, there were no studies with the lowest rating of both applicability (III) and quality (C). Most studies were applicable to the general population of adult patients with RA. Of note, no studies that assessed the effect of omega-3 fatty acids on pain among children with Juvenile RA (JRA) were identified. Table RA: effect size for patient assessment of pain. Intervention Control Trial Source n Source n Effect Size (95% CI) Cleland 16 Max EPA (fish oil) 23 Placebo (-0.60, 0.56) Geusens 17 Fish oil 21 Fish oil 19 Placebo (-0.57, 0.50) Fish oil 20 Kremer 19 Fish oil 17 Placebo (-0.69, 0.61) Kremer 18 Max EPA (fish oil) 17 Placebo (-0.78, 0.51) Magaro 21 Max EPA (fish oil) 10 Placebo (-0.48, 1.29) Nielsen 22 Pikasol (fish oil) 27 Placebo (-1.42, -0.27) Nordstrom 23 Flaxseed oil 11 Placebo (-1.04, 0.63) Skoldstam 25 Max EPA (fish oil) 22 Placebo (-0.56, 0.63) Tulleken 24 Fish oil 13 Placebo (-1.5, 0.06) Pooled Random Effects Estimate* (-0.43, 0.06) *Chi-squared test of heterogeneity p-value =

61 Table Relationship between methodologic quality and applicability for estimates of effect of omega-3 fatty acid consumption on pain among people with rheumatoid arthritis. I Methodological Quality A B C Study n Effect Size(95% CI) Study n Effect Size(95% CI) Cleland (-0.60, 0.56) Kremer (-0.69, 0.61) Geusens (-0.57, 0.50) Applicability II Kremer (-0.78, 0.51) Skoldstam (-0.56, 0.63) Tulleken (-1.5, 0.06) Magaro (-0.48, 1.29) III Figure 3.9. RA: patient assessment of pain. Cleland LG {73} Geusens P {119} Kremer J M {191} Kremer JM {189} Magaro M {215} Nielsen GL {241} Nordstrom DCE {243} Skoldstam L {1579} Tulleken JE {307} Combined Favors treatment Effect size Favors control 45

62 Rheumatoid Arthritis: Swollen Joints Overall effect. The effect of omega-3 fatty acids on swollen joint count in RA was described in 15 studies, 6 of which could be included in meta-analysis. Among these studies, 2 reported significant improvement relative to placebo 29, 33 and 4 reported significant improvement from baseline. 19, 25, 26, 30 18, 22-24, 28, 31, 35, 38 There were no significant effects in 9 studies. In one study, swollen joint count was significantly worse with omega-3 treatment relative to placebo. 16 The pooled random effect estimate for the effect of omega-3 fatty acids on swollen joint count relative to placebo is (95% CI, -0.35, 0.08 (Table 3.17, Figure 3.9). In this analysis, an effect size of 1.0 is equivalent to 3.21 swollen joints. So an effect size of 0.13 is equivalent to a reduction in the swollen joint count by 0.42 joints. Among the 9 studies that were excluded from meta-analysis, 2 reported statistically significant improvements with omega-3 fatty acids and 7 did not. Among the 2 that reported significant improvements, one 29 was of poor methodologic quality (Jadad score =1, concealment of allocation not reported) and the other, 33 although of good methodologic quality (Jadad score = 4, concealment of allocation not reported) was a crossover study and did not include a wash-out period. The effect of omega-3 fatty acids on swollen joints in rheumatoid arthritis has also been assessed in a previously published meta-analysis. 97 This meta-analysis reported improvement favoring fish oil over placebo that was not statistically significant (estimate not reported). Sub-populations. No studies assessed the effect on specific subpopulations. Covariates. One study assessed the effect of two different diets (Western versus modified lacto-vegetarian) combined with omega-3 fatty acids on joint swelling in RA. 26 In this study, among subjects treated with fish oil, there was a reduction in the number of swollen joints among patients on a modified lacto-vegetarian diet relative to a Western diet ( p < 0.01) Effects of dose, source, and exposure duration. One study assessed the effect of two different doses of omega-3 fatty acids on outcomes in RA. 19 In this study, there was a significant improvement in the number of swollen joints at 24 and 36 weeks relative to baseline for subjects treated with a lower dose of fish oil. Among patients treated with a higher dose of fish oil, the improvement relative to baseline was significant only at 24 weeks. There were insufficient data across studies to perform a pooled analysis of dose effect. In one study, plants were the source of omega-3 fatty acids. In this study 23 the effect size of omega-3 fatty acids for swollen joints was (95% CI, -0.90, 0.77). Restricting the pooled analysis to the remaining studies, which a fish source, the pooled random effects estimate of the effect size for swollen joints unchanged at 0.14 (95% CI, -0.36, 0.09). Sustainment of effect. Two studies assessed the sustainment of effects of omega-3 fatty 18, 28 acids on outcomes in RA. In one study, there was no change in swollen joint count in a fish oil-treated arm 1-2 months after discontinuation of the fish oil (p<0.05). In the other study, 100% of the control arm (evening primrose oil) and 80% of the fish oil group returned to baseline or became worse. Although pain, joint swelling, and acute phase reactants were assessed in this study, the parameters on which this assessment was made were not specified. There were insufficient data across studies to perform a pooled analysis of sustainment of effect. 46

63 Quality and applicability. Among studies that entered the meta-analysis, none had both an applicability rating of I (representative of general adult population with rheumatoid arthritis), and a summary quality score of A (Jadad score = 5 with concealment of allocation) (Table 3.18). Similarly, there were no studies with the lowest rating of both applicability (III) and quality (C). Most studies were applicable to the general population of adult patients with RA. Of note, no studies that assessed the effect of omega-3 fatty acids on swollen joints among children with JRA were identified. Table RA: effect size for swollen joint count. Intervention Control Trial Source n Source n Effect Size (95% CI) Cleland 16 Max EPA (fish oil) 23 Placebo (-0.54, 0.62) Kremer 19 Fish oil 20 Fish oil 17 Placebo (-1.30, 0.03) Kremer 18 Max EPA (fish oil) 17 Placebo (-0.66, 0.63) Magalish 20 Omega-3 fatty acid (source not specified) 65 Placebo (-0.51, 0.25) Nielsen 22 Pikasol (fish oil) 27 Placebo (-0.55, 0.55) Nordstrom 23 Flaxseed oil 11 Placebo (-0.90, 0.77) Tulleken 24 Fish oil 13 Placebo (-1.02, 0.50) Pooled Random Effects Estimate (-0.35, 0.08) * Chi-squared test of heterogeneity p-value = 0.81 Table Relationship between methodologic quality and applicability for estimates of effect of omega-3 fatty acid consumption on swollen joints among people with rheumatoid arthritis. I Methodological Quality A B C Study n Effect Size (95% CI) Study n Effect Size (95% CI) Cleland (-0.54, 0.62) Kremer (-1.30, 0.03) Applicability II Kremer (-0.66, 0.63) Tulleken (-1.02, 0.50) III 47

64 Figure RA: swollen joint count. Cleland 16 Kremer 19 Kremer 18 Nielsen 22 Nordstrom 23 Tulleken 24 Combined Favors treatment Favors control Effect size 48

65 Rheumatoid Arthritis: Disease Activity (Erythrocyte Sedimentation Rate) Overall effect. The effect of omega-3 fatty acids on disease activity (Erythrocyte Sedimentation Rate [ESR]) in rheumatoid arthritis was described in 16 studies, 6 of which could be used for meta-analysis. Among these studies, 1 (in which the population had JRA) reported significant improvement relative to placebo 27 and 1 reported significant improvement from baseline. 21 There were no significant effects in 13 studies. 16, 18, 19, 22-24, 25, 28, 29, 32-35, 38 The pooled random effect estimate for the effect of omega-3 fatty acids on ESR relative to placebo is (95% CI, -0.83, 0.19) (Table 3.19, Figure 3.10). In this analysis and effect size of 1.0 is equivalent to mm/hr. So, an effect size of 0.32 is equivalent to a reduction in ESR by 7.6 mm/hr. Among the studies excluded from the meta-analysis, one reported a benefit for omega-3 relative to placebo, but in a special population, JRA; none of the remaining studies reported a significant benefit relative to placebo. Of note, there was significant heterogeneity among these studies (chi-squared test of heterogeneity =0.01). Visual inspection of the Forest plot identified one outlier study. 24 With this study removed from the pooled analysis, the pooled random effects estimate for the effect of omega-3 fatty acids on ESR relative to placebo is (95% CI, -0.37, 0.23), and the chisquared test for heterogeneity is not significant (p =.77). The outlier study is similar to the other studies in the pooled analysis in terms of study design, source, dose, and duration of omega-3 fatty acid treatment. The characteristics of the study population in the outlier study are also similar to those of the other studies in the pooled analysis in terms of age, disease duration, number of swollen joints, and number of tender joints. However, the baseline ESR and C- Reactive Protein (CRP) values for the control group in the outlier study were significantly higher than for the experimental group (p<0.05). This observation suggests that the disease activity may have been higher in the control group than in the experimental group, which could bias toward a more favorable estimate of the effect of omega-3 fatty acids. The effect of omega-3 fatty acids on ESR in rheumatoid arthritis has also been assessed in a previously published meta-analysis. 97 This meta-analysis reported improvement with fish oil relative to placebo; however, this improvement was not statistically significant (estimate not reported). Sub-populations. One study assessed the effect of cod liver oil on ESR among children with JRA. This study demonstrated a significant reduction in ESR for cod liver oil relative to placebo. 27 Covariates. The effect of covariates on the efficacy of omega-3 fatty acids was not specifically assessed in any of the studies identified. Effects of dose, source, and exposure duration.one study assessed the effect of two different doses of omega-3 fatty acids on outcomes in RA. 19 In this study, there was a significant improvement in ESR at 24 and 36 weeks relative to baseline for subjects treated with a lower dose of fish oil. Among patients treated with a higher dose of fish oil, the improvement relative to baseline was significant only at 24 weeks. There were insufficient data across studies to perform a pooled analysis of dose or source effect. 49

66 In one study, plants were the source of omega-3 fatty acids. In this study, 23 the effect size of omega-3 fatty acids for ESR was 0.13 (95% CI, -0.71, 0.96). Restricting the pooled analysis to the remaining studies, which used a fish source, the pooled random effects estimate of the effect size for ESR was 0.41 (95% CI, -0.99, 0.18). Sustainment of effect.the sustainment of effects of omega-3 fatty acids on ESR or CRP in RA was not clearly described in any studies. In one study, % of the control arm (evening primrose oil) and 80% of the fish oil group returned to baseline or became worse. Although pain, joint swelling, and ESR were assessed in this study, the parameters on which this assessment was made were not specified. Quality and applicability. Among studies that entered the meta-analysis, none had both an applicability rating of I (representative of general adult population with rheumatoid arthritis), and a summary quality score of A (Jadad score = 5 with concealment of allocation) (Table 3.20). Similarly, there were no studies with the lowest rating of both applicability (III) and quality (C). Most studies were applicable to the general population of adult patients with RA. Of note, one study that assessed the effect of omega-3 fatty acids on ESR among children with JRA was identified. Table RA: effect size for ESR. Intervention Control Trial Source n Source n Effect Size (95% CI) Kremer 18 Max EPA (fish oil) 17 Placebo (-1.1, 0.21) Magaro 21 Max EPA (fish oil) 10 Placebo (-1.04, 0.72) Nielsen 22 Pikasol (fish oil) 27 Placebo (-0.49, 0.61) Nordstrom 23 Flaxseed oil 11 Placebo (-0.71, 0.96) Skoldstam 25 Max EPA (fish oil) 22 Placebo (-0.55, 0.64) Tulleken 24 Fish oil 13 Placebo (-2.71, -0.92) Pooled Random Effects Estimate (-0.83, 0.19) * Chi-squared test of heterogeneity p-value =

67 Table Relationship between methodologic quality and applicability for estimates of effect of omega-3 fatty acid consumption on ESR among people with rheumatoid arthritis. I Methodological Quality A B C Study n Effect Size(95% CI) Study n Effect Size(95% CI) Kremer (-1.10, 0.21) Applicability II III Skoldstam (-0.55, 0.64) Tulleken (-2.71, -0.92) Magaro (-1.04, 0.72) Figure RA: ESR. Kremer 18 Magaro 21 Nielsen 22 Nordstrom 23 Skoldstam 25 Tulleken 24 Combined -2.7 Favors Favors control 1 treatment Effect size 51

68 Rheumatoid Arthritis: Patient s Global Assessment Overall effect. The effect of omega-3 fatty acids on patient s global assessment in RA was described in 8 studies, 5 of which could be used for meta-analysis. Among these studies, 1 reported significant improvement relative to placebo, 17 and 3 reported significant improvement from baseline. 25, 26, 30 There were no significant effects in 4 studies. 16, 18, 19, 31 The pooled random effect estimate for the effect of omega-3 fatty acids on patient s global assessment relative to placebo is (95% CI, -0.90, 0.30) (Table 3.21, Figure 3.11). In this analysis, an effect size of 1.0 is equivalent to 0.7 units on the patient global assessment scale. So, an effect size of 0.30 is equivalent to a decrease on the scale by 0.21 units. None of the studies that were excluded from the meta-analysis demonstrated a significant of omega-3 fatty acids on patient s global assessment. Of note, there was significant heterogeneity among these studies (chi-squared test of heterogeneity =0.002). Visual inspection of the Forest plot identified one outlier study. 17 With this study removed from the pooled analysis, the pooled random effect estimate for the effect of omega-3 fatty acids on patient global assessment relative to placebo is (95% CI, -0.36, 0.31) and the chi-squared test for heterogeneity is not significant (p =.76). On qualitative review of the outlier study, we could find no characteristics that differed from the other studies. The outlier study is similar to the other studies in the pooled analysis in terms of study design, source, and dose of omega-3 fatty acid. The characteristics of the study population in the outlier study are similar to those of the other studies in the pooled analysis in terms of age, disease duration, number of swollen joints, and number of tender joints. Although the study duration is longer (12 months) in the outlier study than in the other studies (3-9 months), a common time point for assessment (3 months) was used in the pooled analysis. The effect of omega-3 fatty acids on patient s global assessments in RA has also been assessed in a previously published meta-analysis. 97 This meta-analysis reported improvement with fish oil relative to placebo; however, this improvement was not statistically significant (estimate not reported). Sub-populations. No studies assessed the effects across sub-populations. Covariates. One study assessed the effect of combining different diets (Western versus modified lacto-vegetarian) with omega-3 fatty acids on patient s global assessment in RA. 26 In this study, among subjects treated with fish oil, there was a reduction in patient s global assessment among patients on a modified lacto-vegetarian diet relative to a Western diet ( p<0.01) Effects of dose, source, and exposure duration. One study assessed the effect of different doses of omega-3 fatty acids on outcomes in RA. 19 In this study, the effect of fish oil on patient s global assessment did not differ between doses. There were insufficient data across studies to perform a pooled analysis of dose or source effect. In one study plants were the source of omega-3 fatty acids. In this study, 23 the effect size of omega-3 fatty acids for patient global assessment was 0.26 (95% CI, -0.58, 1.10). Restricting the pooled analysis to the remaining studies, which used a fish source, the pooled random effects estimate of the effect size for patient global assessment was 0.42 (95% CI, -1.09, 0.26). 52

69 One study assessed the effects of omega-3 fatty acids on outcomes in RA for different durations of exposure. 19 In this study, there was no effect on patient s global assessment at 24 and 36 weeks, although statistical testing of the effect between these time points was not performed. Sustainment of effect. One study assessed the sustainment of effects of omega-3 fatty acids on patient s global assessment in RA. 18 In this study, patient s global assessment worsened in a group that had been in a fish oil-treated arm, 3 months after discontinuation of the fish oil (p<0.05). Quality and applicability. Among studies that entered the meta-analysis, none had both an applicability rating of I (representative of general adult population with rheumatoid arthritis), and a summary quality score of A (Jadad score = 5 with concealment of allocation) (Table 3.22). Similarly there were no studies with the lowest rating of both applicability (III) and quality (C). Most studies were applicable to the general population of adult patients with RA. Of note, no studies that assessed the effect of omega-3 fatty acids on patient s global assessment among children with JRA were identified. Table RA: effect size for patient global assessment. Intervention Control Trial Source n Source n Effect Size (95% CI) Geusens 17 Fish oil 21 Fish oil 19 Placebo (-1.97, -0.79) Fish oil 20 Kremer 19 Fish oil 17 Placebo (-0.78, 0.52) Kremer 18 Max EPA (fish oil) 17 Placebo (-0.89, 0.41) Nordstrom 23 Flaxseed oil 11 Placebo (-0.58, 1.10) Skoldstam 25 Max EPA (fish oil) 22 Placebo (-0.49, 0.71) Pooled Random Effects Estimate (-0.90, 0.30) * Chi-squared test of heterogeneity p-value = Table Relationship between methodologic quality and applicability for estimates of effect of omega-3 fatty acid consumption on global assessment among people with rheumatoid arthritis. I Methodological Quality A B C Study n Effect Size (95% CI) Study n Effect Size(95% Ci) Geusens (-1.97, -0.79) Kremer (-0.78, 0.52) Applicability II III Kremer (-0.89, 0.41) Skoldstam (-0.49, 0.71) 53

70 Figure RA: patient global assessment. Geusens 17 Kremer 19 Kremer 18 Nordstrom 23 Skoldstam 25 Combined Favors treatment Favors control Effect size 54

71 Rheumatoid Arthritis: Joint Damage Overall effect. We identified one study that assessed the effect of omega-3 fatty acids on joint damage in RA. 29 In this study, the Larsen score of radiographic damage was not affected by administering the omega-3 fatty acids in the form of a diet high in fish. Rheumatoid Arthritis: Tender Joint Count Overall effect. The effect of omega-3 fatty acids on tender joint count in RA has been assessed in a previously published meta-analysis. 97 Inclusion criteria for this meta-analysis were 1) double blind, placebo controlled trial, 2) use of at least one of seven predetermined outcome measures, including tender joint count, 3) results reported for both placebo and treatment groups at baseline and follow-up, 4) randomization, and 5) parallel or cross-over design. A Medline search through 1991 identified 10 trials that met the inclusion criteria, 6 of which were analyzed for tender joint count. The rate difference between fish oil and placebo for tender joint count was 2.9 ( 95% CI, -3.8, -2.1). Analysis of subpopulations and covariates, effects of dose, source, and exposure duration, and sustainment of effect were not addressed in this meta-analysis. Rheumatoid Arthritis: Effect on Anti-inflammatory/ Immunosuppressive Drug Requirement Overall effect. We identified 7 studies that assessed the effect of omega-3 fatty acids on anti-inflammatory and/or immunosuppressive drug requirements among patients with RA. All 7 studies assessed the effect on requirement for anti-inflammatory drugs. Among these studies, there was significant improvement relative to placebo for omega-3 treated subjects in 3, significant improvement relative to baseline requirements in 3, 25, 26, 28 and no difference in NSAID requirement in One study, which assessed the effect of omega-3 fatty acids on steroid requirements, demonstrated significant improvement relative to placebo. 30 We did not identify any studies that assessed the effect of omega-3 fatty acids on disease modifying antirheumatic drug (DMARD) requirement. Sub-populations. Not assessed in any identified studies. Covariates. Not assessed in any identified studies. Effects of dose, source, and exposure duration. The effects of dose, source, and exposure duration were not specifically assessed in any of the studies. Sustainment of effect. Two studies demonstrated that the effect of omega-3 fatty acids on 30, 31 the requirement for NSAIDs in RA was not sustained. 55

72 RENAL DISEASE Summaries of all renal disease studies we evaluated can be found in Appendix C.4. Renal Disease: Clinical Effect Overall effect. The effect of omega-3 fatty acids on each of the following was assessed in patients with renal disease: serum creatinine, creatinine clearance, progression to end stage renal disease (ESRD), hemodialysis graft thrombosis/patency, and mortality. A total of studies were identified that reported these outcomes. There were insufficient data to perform meta-analysis on any of the outcomes. Effects on serum creatinine were described in 4 studies: 1 reported a statistically significant improvement with fish oil relative to placebo, 98 1 reported no effect, 99 and 2 reported 100, 101 worsening. Among the studies that reported worsening, neither reported testing of statistical significance between the omega-3 and control arms, and in one, there was worsening for both the omega-3 and control group. Creatinine clearance was reported in 3 studies: 1 reported a statistically significant improvement with fish oil relative to placebo, 98 and 2 reported worsening. 100, 101 Among the studies that reported worsening, neither reported testing of statistical significance between the omega-3 and control arms, and in one, there was worsening for both the omega-3 and control groups. Progression to ESRD was reported in 2 studies: 98, 100 one demonstrated a favorable effect for fish oil relative to placebo, 98 and the other demonstrated no effect. Hemodialysis graft thrombosis/patency was described in 2 studies. 102, 103 In one, graft patency was significantly better for fish oil than for placebo. 102 There were no graft thromboses in either the omega-3 fatty acid or the control groups. 103 Mortality was reported in two studies. 98, 104 Statistical testing for between group mortality rates was not reported in either. In one, mortality over 5 years was 2.0% in the placebo group and 1.8% in the omega-3 group; 98 in the other, the mortality over 5 years was zero in a low-dose fish oil group and 6% in a high-dose fish oil group. 104 Meta-Analysis. Across the studies identified, only three were sufficiently homogeneous in terms of the population studies and the outcomes reported to consider for meta-analysis. These studies evaluated the effects of omega-3 fatty acids on Immunoglobulin A(IgA) nephropathy. 98, 100, 101 These studies, along with two other studies 117,118 that were identified but not included in this report because they did not meet our inclusion criteria, have been evaluated in a previously published meta-analysis. 105 This meta-analysis calculated effect sizes for treatment effect based on either serum creatinine concentration or creatinine clearance. Although the pooled effect size for the five studies was positive (i.e. favoring treatment over control), it was small (0.25) and not statistically significant (p=0.27). 56

73 Sub-populations. No studies that assessed the differential effect of omega-3 fatty acids across distinct subpopulations of renal disease were identified. Among the studies identified, the renal disease in the study sample was IgA nephropathy in four, 98, 100, 101, 104 lupus nephritis in one, 99 glomerular disease in one, , 103 and ESRD requiring dialysis in two. Covariates. The effect of omega-3 fatty acids on covariates was not assessed in any of the identified studies. Dose and source effect. Dose and source effects of omega-3 fatty acids were not assessed in any of the identified studies. Exposure duration. Effect of exposure duration of omega-3 fatty acids was not assessed in any of the identified studies. Sustainment of effect. Sustainment of effect after discontinuation of omega-3 fatty acids was not assessed in any of the identified studies. Renal Disease: Effect on Corticosteroid/Other Immunosuppressive Drug Requirement We did not identify any studies that assessed the effects of omega-3 fatty acids on requirements for corticosteroids or other immunosuppressive drugs. SYSTEMIC LUPUS ERYTHEMATOSUS Summaries of all systemic lupus erythematosus studies we evaluated can be found in Appendix C.5. Systemic Lupus Erythematosus: Clinical Effect Overall effect. The effect of omega-3 fatty acids on each of the following was assessed in patients with SLE: disease activity, damage, and patient perception of disease. A total of 3 studies was identified that reported disease activity; 99, 107, 108 no studies that assessed the other outcomes were identified. There were insufficient data to perform meta-analysis on disease activity. Disease activity was described using clinical and laboratory scores. Improvement in disease activity was reported in one study, which used a clinical score developed for that study (validity of score not described). 107 The other studies reported no effect on the SLE Disease Activity Index (SLEDAI) 99 or on another clinical score developed for the study (validity of instrument not described). 108 Levels of anti-dna antibodies and complement levels were assessed in two of the studies; 99, 108 neither demonstrated an omega-3 fatty acid effect. No studies were identified that assessed effect on damage or patient perception of disease. 57

74 Sub-populations. No studies that assessed the differential effect of omega-3 fatty acids across distinct subpopulations of SLE were identified. Covariates. The effect of omega-3 fatty acids on covariates were not assessed in any of the identified studies. Dose and source effect. Dose and source effects of omega-3 fatty acids were not assessed in any of the identified studies. Exposure duration. Effect of exposure duration of omega-3 fatty acids was not assessed in any of the identified studies. Sustainment of effect. One study was designed to evaluate for sustainment of effect after discontinuation of omega-3 fatty acids. 108 However, in this study, no main effect was demonstrated before discontinuation of the omega-3 fatty acid. Systemic Lupus Erythematosus: Effect on Steroid/Other Immunosuppressive Drug Requirement We identified one study that assessed the effects of omega-3 fatty acids on requirements for corticosteroids. 99 In this study, omega-3 fatty acids had no effect on steroid requirements. We identified no studies that assessed the effects of omega-3 fatty acids on requirements for other immunosuppressive drugs. BONE DENSITY/OSTEOPOROSIS Summaries of all bone density/osteoporosis studies evaluated can be found in Appendix C.6. Bone Density/Osteoporosis: Clinical Effect Overall effect. The effects of omega-3 fatty acids on bone mineral density and fracture rate were assessed. In total, 5 studies described in 4 reports were identified that reported bone mineral density; no studies of fracture rate were identified. There were insufficient data to perform meta-analysis on bone mineral density. Improvement in bone mineral density for omega-3 fatty acids relative to placebo was described in one study; 111 improvement relative to baseline was described in one study. 110 In two 109, 112 studies, omega-3 fatty acids had no effect on bone mineral density. Sub-populations. One report described separate studies performed in pre-menopausal and post-menopausal women. No effect was seen in either population. Covariates. The effect of omega-3 fatty acids on covariates was not assessed in any of the identified studies. 58

75 Dose and source effect. Dose and source effects of omega-3 fatty acids were not assessed in any of the identified studies. Exposure duration. Effect of exposure duration of omega-3 fatty acids was not assessed in any of the identified studies. Sustainment of effect. Sustainment of effect after discontinuation of omega-3 fatty acids was not assessed in any of the identified studies. Publication Bias There was no evidence of publication bias on the funnel plots and adjusted rank correlation testing (not shown) performed for studies that entered meta-analysis. Adverse Events Among 83 articles across the six topic areas of this report that were reviewed for adverse events, 28 reported adverse events, which are summarized in Table Table Summary of reported adverse events.* Adverse Event Total # of studies N for Omega 3 Sample size N for Placebo/ Control Adverse event count N for Omega 3 N for Placebo/ Control Adverse event rate Omega 3 Adverse event rate Placebo Clinical bleeding 1 73 NR** % ---- GI complaint or nausea % 4.96% Diarrhea % 4.81% Headaches % 0.00% Withdrawal due to adverse event % 3.95% Dermatological % 6.29% N = number of individuals with an adverse event. **Not reported. No placebo arm reported on clinical bleeding. 59

76 Chapter 4. Discussion Overview We screened 4,212 titles, from which we reviewed 1,097 full text articles. Among these, 83 articles met our inclusion criteria; 34 for diabetes/ metabolic syndrome, 13 for inflammatory bowel disease, 21 for rheumatoid arthritis, 9 for renal disease, 3 for systemic lupus erythematosus and 4 for bone density and fractures. All articles except one were randomized controlled trials; one was an observational study of bone density. Most of the studies assessed the effect of omega-3 fatty acids in the form of fish oil; however, some assessed the effect of diets rich in fish. Across all conditions and studies, only 4 studies evaluated omega-3 fatty acids derived from plant oils; three for diabetes 65,66,70 and 1 for RA. 23 Few studies assessed dose or source effect, effect of treatment duration, or the sustainment of effect after discontinuation of omega-3 fatty acid consumption. Main Findings Diabetes/metabolic syndrome. Among 13 studies of type II diabetes or the metabolic syndrome, that were assessed by meta-analysis, omega-3 fatty acids had a favorable effect on triglyceride levels relative to placebo (pooled random effects estimate: ; 95% CI, , ) but had no effect on total cholesterol, HDL cholesterol, LDL cholesterol, fasting blood sugar, or glycosylated hemoglobin, by meta-analysis. Omega-3 fatty acids had no effect on plasma insulin or insulin resistance in type II diabetics or patients with the metabolic syndrome, by qualitative analysis of four studies. These results are consistent with the results of another meta-analysis for fish oil, 116 which found significant triglyceride-lowering and LDL-raising effects and no significant effect on fasting blood glucose, glycosylated hemoglobin, total cholesterol, or HDL cholesterol among diabetics. Although the analysis presented here did not find a significant effect on LDL, the point estimate is consistent with a LDL raising effect and the confidence interval barely crosses null (95% CI, -1.02, 11.25). The effects of omega-3 fatty acids on triglycerides in diabetics presented here and elsewhere are consistent with the triglyceride-lowering effects of omega-3 fatty acids that have been demonstrated for the general population and are being detailed in a separate evidence report Effects of Omega-3 Fatty Acids on Cardiovascular Risk Factors (in preparation at the New England Medical Center Evidence Based Practice Center). Regarding the lack of effect that omega-3 fatty acids have on insulin sensitivity, it is possible that any beneficial effects of omega- 3 fatty acids on insulin sensitivity could be attenuated by their high calorie content. Inflammatory bowel disease. Among 13 studies reporting outcomes in patients with inflammatory bowel disease, variable effects of omega-3 fatty acids on clinical score, sigmoidoscopic score, histologic score, induced remission, and relapse were reported. In ulcerative colitis, omega-3 fatty acids had no effect on the relative risk of relapse in a metaanalysis of 3 studies. There was a statistically non-significant reduction in requirement for Note: Appendixes and Evidence Tables cited in this report are provided electronically at 61

77 corticosteroids for omega-3 fatty acids relative to placebo in 2 studies. No studies evaluated the effect of omega-3 fatty acids on requirement for other immunosuppressive agents. Rheumatoid arthritis. Among 9 studies reporting outcomes in patients with rheumatoid arthritis, omega-3 fatty acids had no effect on patient report of pain, swollen joint count, ESR, and patient s global assessment by meta-analysis. The one study that assessed the effect on joint damage found no effect. In a qualitative analysis of 7 studies that assessed the effect of omega-3 fatty acids on anti-inflammatory drug or corticosteroid requirement, 6 demonstrated reduced requirement for these drugs. No studies assessed the effect on requirements for disease modifying anti-rheumatic drugs. None of the studies used a composite score that incorporates both subjective and objective measures of disease activity, such as the American College of Rheumatology response criteria. A previously performed meta-analysis 97 reached the same conclusions for swollen joint count, ESR, and patient s global assessment. That meta-analysis found a statistically significant improvement in tender joint count compared to placebo (rate difference= -2.9, 95% CI 3.8, - 2.1). Renal disease. In a qualitative analysis of nine studies that assessed the effect of omega-3 fatty acids in renal disease, there were varying effects on serum creatinine and creatinine clearance; one study demonstrated less progression to end stage renal disease with omega-3 fatty acids relative to control. In a single study that assessed the effect on hemodialysis graft patency, graft patency was significantly better with fish oil than with placebo. No studies that assessed the effects of omega-3 fatty acids on requirements for corticosteroids or other immunosuppressive drugs for the treatment of renal disease were identified. Systemic lupus erythematosus. Among 3 studies that assessed the effects of omega-3 fatty acids in SLE, variable effects on clinical activity were reported. No studies were identified that assessed effect on damage or patient perception of disease. Omega-3 fatty acids had no effect on corticosteroid requirements in 1 study. No studies were identified that assessed the effects of omega-3 fatty acids on requirements for other immunosuppressive drugs for SLE. None of the studies used a measure of disease activity that incorporates both subjective and objective measures of disease activity. Bone mineral density/fracture. Among five studies described in 4 reports the effect of omega-3 fatty acids on bone mineral density was variable. No studies that assessed the effect of omega-3 fatty acids on fracture were identified. Dose, source, duration effects and sustainment of effect. Among studies that assessed the effects of omega-3 fatty acids in diabetes, there was no dose effect for any outcome by metaregression. There are insufficient data to draw conclusions about source or duration effects, or about sustainment of effect. Adverse events. Across all conditions, the incidence of gastrointestinal complaints or nausea, diarrhea, and headaches appears to be higher among patients receiving omega-3 fatty acids than among those in control groups. Strong conclusions cannot be drawn from this 62

78 observation because adverse events were not reported in a standard manner in clinical trials, either in terms of the events defined or the frequency with which they were recorded. Additionally, the underlying conditions being studied will affect the rates of specific adverse events. Conclusions The quantity and strength of evidence for effects of omega-3 fatty acids on outcomes in the conditions assessed varies greatly. The findings of many studies among type II diabetics provide strong evidence that omega-3 fatty acids reduce serum triglycerides but have no effect on total cholesterol, HDL cholesterol and LDL cholesterol. For rheumatoid arthritis, the available evidence suggests that omega-3 fatty acids reduce tender joint counts and may reduce requirements for corticosteroids, but does not support an effect of omega-3 fatty acids on other clinical outcomes. There are insufficient data available to draw conclusions about the effects of omega-3 fatty acids on inflammatory bowel disease, renal disease, SLE, bone density, or fractures or the effects of omega-3 fatty acids on insulin resistance among type II diabetics. Future Research We offer the following observations and recommendations regarding future research on the effects of omega-3 fatty acids on lipids and glycemic control in type II diabetes and the metabolic syndrome and on inflammatory bowel disease, rheumatoid arthritis, renal disease, systemic lupus erythematosus, and osteoporosis. 1. Additional research on the effects of omega-3 fatty acids need to be performed on inflammatory bowel disease, renal disease, SLE, bone density, or fractures or the effects of omega-3 fatty acids on insulin resistance among type II diabetics before recommendations regarding the use of omega-3 fatty acids for these conditions can be made. 2. Studies of inflammatory bowel disease that include patients with both Crohn s disease and ulcerative colitis should report data separately for these groups. 3. Studies that assess the effects of omega-3 fatty acids should use standard validated instruments to assess clinical outcomes. 4. Trials that assess the effects of omega-3 fatty acids should be designed to evaluate the effect of source, dose, treatment duration, and the sustainment of effect after discontinuation of omega-3 fatty acid consumption. 5. Studies of omega-3 fatty acids should explicitly define both the quantity of the omega-3 fatty acid source and of the specific omega-3 fatty acids present in a study dose of that source. 63

79 6. Trials of omega-3 fatty acids should include a baseline assessment of dietary omega-3 and omega-6 fatty acid intake. 7. In controlled trials that assess the effects of omega-3 fatty acids, analysis should include and report explicit testing of the effects of the omega-3 fatty acid relative to the control substance. 8. In studies that use a crossover design, outcome data for all study arms should be reported at the end of each treatment period. 64

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83 54. Belluzzi A, Brignola C, Campieri M, Pera A, Boschi S, Miglioli M. Effect of an entericcoated fish-oil preparation on relapses in Crohn's disease. New England Journal of Medicine 1996;334(24): Lorenz-Meyer H, Bauer P, Nicolay C, Schulz B, Purrmann J, Fleig W, et al. Omega-3 fatty acids and low carbohydrate diet for maintenance of remission in Crohn's disease. A randomized controlled multicenter trial. Study Group Members (German Crohn's Disease Study Group). Scandinavian Journal of Gastroenterology 1996;31(8): Shimizu H, Ohtani K, Tanaka Y, Sato N, Mori M, Shimomura Y. Long-term effect of eicosapentaenoic acid ethyl (EPA-E) on albuminuria of non-insulin dependent diabetic patients. Diabetes Research & Clinical Practice 1995;28(1): Annuzzi G, Rivellese A, Capaldo B, Di Marino L, Iovine C, Marotta G, et al. A controlled study on the effects of n-3 fatty acids on lipid and glucose metabolism in noninsulin-dependent diabetic patients. Atherosclerosis 1991;87(1): Chan D, Watts G, Mori T, Barrett P, Beilin L, Redgrave T. Factorial study of the effects of atorvastatin and fish oil on dyslipidaemia in visceral obesity. European Journal of Clinical Investigation 2002;32(6): Dunstan D, Mori T, Puddey I, Beilin L, Burke V, Morton A, et al. Exercise and fish intake: Effects on serum lipids and glycemic control for type 2 diabetics. Cardiology Review 1998;15(8): Hendra T, Britton M, Roper D, Wagaine- Twabwe D, Jeremy J, Dandona P, et al. Effects of fish oil supplements in NIDDM subjects. Controlled study. Diabetes Care 1990;13(8): Morgan W, Raskin P, Rosenstock J. A comparison of fish oil or corn oil supplements in hyperlipidemic subjects with NIDDM. Diabetes Care 1995;18(1): Pelikanova T, Kohout M, Valek J, Kazdova L, Base J. Metabolic effects of omega-3 fatty acids in type 2 (non-insulin-dependent) diabetic patients. Annals of the New York Academy of Sciences 1993;683: Petersen M, Pedersen H, Major-Pedersen A, Jensen T, Marckmann P. Effect of fish oil versus corn oil supplementation on LDL and HDL subclasses in type 2 diabetic patients. Diabetes Care 2002;25(10): Sirtori C, Crepaldi G, Manzato E, Mancini M, Rivellese A, Paoletti R, et al. One-year treatment with ethyl esters of n-3 fatty acids in patients with hypertriglyceridemia and glucose intolerance: reduced triglyceridemia, total cholesterol and increased HDL-C without glycemic alterations. Atherosclerosis 1998;137(2): Alekseeva R, Sharafetdinov K, Kh Plotnikova OA, Meshcheriakova V, Mal'tsev G, Kulakova S. Effects of a diet including linseed oil on clinical and metabolic parameters in patients with type 2 diabetes mellitus. Voprosy Pitaniia 2000;69(6): Meshcheriakova V, Plotnikova O, Sharafetdinov K, Kh AR, Mal'tsev G, Kulakova S. Comparative study of effects of diet therapy including eiconol or linseed oil on several parameters of lipid metabolism in patients with type 2 diabetes mellitus. Voprosy Pitaniia 2001;70(2): Morgan WA. The effects of fish oil versus corn oil on subjects with hyperlipidemia and type ii, noninsulin-dependent diabetes mellitus (Fatty acids). Dissertation Abstracts International 51-06, Section: B: Patti L, Maffettone A, Iovine C, Marino L, Annuzzi G, Riccardi G, et al. Long-term effects of fish oil on lipoprotein subfractions and low density lipoprotein size in noninsulin-dependent diabetic patients with hypertriglyceridemia. Atherosclerosis 1999;146(2): Rivellese A, Maffettone A, Iovine C, Di Marino L, Annuzzi G, Mancini M, et al. Longterm effects of fish oil on insulin resistance and plasma lipoproteins in NIDDM patients with hypertriglyceridemia. Diabetes Care 1996 ;19(11):

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85 85. McVeigh G, Brennan G, Cohn J, Finkelstein S, Hayes R, Johnston G. Fish oil improves arterial compliance in non-insulin-dependent diabetes mellitus. Arteriosclerosis & Thrombosis 1994;14(9): Puhakainen I, Ahola I, Yki-Jarvinen H. Dietary supplementation with n-3 fatty acids increases gluconeogenesis from glycerol but not hepatic glucose production in patients with non-insulin-dependent diabetes mellitus. American Journal of Clinical Nutrition 1995;61(1): Schectman G, Kaul S, Kissebah A. Effect of fish oil concentrate on lipoprotein composition in NIDDM. Diabetes 1988;37(11): Schwab U, Sarkkinen E, Lichtenstein A, Li Z, Ordovas J, Schaefer E, et al. The effect of quality and amount of dietary fat on the susceptibility of low density lipoprotein to oxidation in subjects with impaired glucose tolerance. European Journal of Clinical Nutrition 1998;52(6): Sirtori C, Paoletti R, Mancini M, Crepaldi G, Manzato E, Rivellese A, et al. N-3 fatty acids do not lead to an increased diabetic risk in patients with hyperlipidemia and abnormal glucose tolerance. Italian Fish Oil Multicenter Study. American Journal of Clinical Nutrition 1997;65(6): Vandongen R, Mori T, Codde J, Stanton K, Masarei J. Hypercholesterolaemic effect of fish oil in insulin-dependent diabetic patients. Medical Journal of Australia 1988;148(3): Vessby B, Boberg M. Dietary supplementation with n-3 fatty acids may impair glucose homeostasis in patients with non-insulindependent diabetes mellitus. Journal of Internal Medicine 1990;228(2): Chan D, Watts G, Barrett P, Beilin L, Redgrave T, Mori T. Regulatory effects of HMG CoA reductase inhibitor and fish oils on apolipoprotein B-100 kinetics in insulinresistant obese male subjects with dyslipidemia. Diabetes 2002;51(8): Dunstan D, Mori T, Puddey I, Beilin L, Burke V, Morton A, et al. The independent and combined effects of aerobic exercise and dietary fish intake on serum lipids and glycemic control in NIDDM. A randomized controlled study. Diabetes Care 1997;20(6): Varghese T, Coomansingh D. Clinical response of ulcerative colitis with dietary omega-3 fatty acids: a double-blind randomized study. British Journal of Surgery 2000;87(1): Hawthorne A, Daneshmend T, Hawkey C, Belluzzi A, Everitt S, Holmes G, et al. Treatment of ulcerative colitis with fish oil supplementation: a prospective 12 month randomised controlled trial. Gut 1992;33(7): Sperling R, Weinblatt M, Robiin J, Ravalese J, Hoover R, House Fea. Effects of dietary supplementation with marine fish oil on leukoeyte lipid mediators and function in rheumatoid rthritis. Arthritis Rheum 1987;30: Fortin P, Lew R, Liang M, Wright E, Beckett L, Chalmers T, et al. Validation of a metaanalysis: The effects of fish oil in rheumatoid arthritis. Journal of Clinical Epidemiology 1995;48(11): Donadio J, Jr, Bergstralh E, Offord K, Spencer D, Holley K. A controlled trial of fish oil in IgA nephropathy. Mayo Nephrology Collaborative Group. New England Journal of Medicine 1994;331(18): Clark W, Parbtani A, Naylor C, Levinton C, Muirhead N, Spanner E, et al. Fish oil in lupus nephritis: clinical findings and methodological implications. Kidney International. 1993;44(1): Bennett W, Walker R, Kincaid-Smith P. Treatment of IgA nephropathy with eicosapentanoic acid (EPA): a two-year prospective trial. Clinical Nephrology 1989;31(3):

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87 72

88 Acronyms AA Arachidonic acid Mo Month Ab Antibody n Number AHRQ Agency for Healthcare Research and n-3 Omega-3 Quality AI Adequate intake n-6 Omega-6 ALA Alpha-linolenic acid NA Not applicable AMDR Acceptable macronutrient distribution ranges NHANES III The Third National Health and Nutrition Examination ANCOVA Analysis of covariance NCI National Cancer Institute ANOVA Analysis of variance NEI National Eye Institute Ca Calcium NEMC New England Medical Center CCT Controlled clinical trial NHANES National Health and Nutrition Examination CI Confidence interval NHLBI National Heart, Lung and Blood Institute CRP C-reactive protein NIAAA National Institute of Alcohol Abuse and Alcoholism CSFII Continuing Food Survey of Intakes by Individuals NIAID National Institute of Allergy and Infectious Diseases d day NIAMS National Institute of Arthritis and Musculoskeletal and Skin Diseases D6D Delta-6 Desaturase NICHD National Institute of Child Health and Human Development DGLA Dihomo-gamma-linolenic acid NIDDK National Institute of Diabetes and Digestive and Kidney Diseases DHA Docosahexaenoic acid NIH National Institutes of Health DPA Docosapentaenoic acid NNH Number needed to harm DRI Dietary Reference Intake NR Not reported Ds-DNA Double-stranded DNA NSAIDS Non-Steroidal Anti-Inflammatory Drugs EF Effect size ODS Office of Dietary Supplements EFA Essential fatty acid PG Prostaglandin EPA Eicosapentaenoic acid PGD Prostaglandin-D EPC Evidence-Based Practice Center PGE Prostaglandin-E ESR Erythrocyte sedimentation rate PGF Prostaglandin-F FNB Food and Nutrition Board PGL Prostaglandin-L g grams PGH Prostaglandin-H GI Gastrointestinal PUFA Polyunsaturated fatty acid GLA Gamma-linolenic acid QRF Quality review form HDL High density lipoprotein RA Rheumatoid arthritis IBD Inflammatory bowel disease RCT Randomized controlled trial IL-1ß Interleukin 1ß RDA Recommended daily allowances JRA Juvenile rheumatoid arthritis RXT Randomized crossover trial IOM Institute of Medicine Sd Standard deviation LA Linoleic acid SCEPC Southern California Evidence-Based Practice Center LC PUFA Long-chain polyunsaturated fatty acid SLE Systemic lupus erythematosus LDL Low density lipoprotein SEM Standard errors of the means MA Metaanalysis TEP Technical expert panel MANOVA Multivariate analysis of variance TNF-a Tumor necrosis factor-a MeSH Term Medical Subject Headings Term TX Treatment mg/dl Milligrams per deciliter TXA Thromboxane-A min Minutes UCLA University of California, Los Angeles VLCFA Very long chain fatty acid VLN-3FA Very long chain n-3 fatty acids wk Week 145

89

90 Listing of Excluded Studies Rejected on Abstract Review AnonymousDietary fats and oils in human nutrition; report of an expert consultation held in Rome. FAO Food and Nutrition Paper 1977; AnonymousThe effect of omega-3 fatty acids. Therapiewoche 1990;40: AnonymousFish, diabetes, and the arterial wall. Lancet 1989;2:1332- AnonymousFish oil for type 2 diabetes. Health News 2000;6:7- AnonymousFish oils and diabetic microvascular disease. Lancet 1990;335: AnonymousIncreasing fish oil intake - Any net benefits? Drug & Therapeutics Bulletin 1996;34: AnonymousItalian Society of Dietetics and Clinical Nutrition. XII national conference - lipids in dietetics and clinical nutrition, Torino, Italy, 16-November, Minerva Gastroenterologica e Dietologica 1997; AnonymousLectures given at the 9th Aachen Dietetics Further Education Meeting, September, Ernahrung and Medizin 2002; AnonymousManagement of hyperlipidaemia. Drug & Therapeutics Bulletin 1996;34: AnonymousNutrition and chronic inflammatory bowel disease. Medizinische Welt 2001;52: AnonymousUpdate on inflammatory bowel disease. Pharmaceutical Journal 2001;267: Abrahamsson H, Gustafson A, Ohlson R: Polyunsaturated fatty acids in hyperlipoproteinemia. 1. Influences of a sucrose-rich diet on fatty acid composition of serum lipoprotein lipids. Nutrition and Metabolism 1974; Adam O: Nutritional influences on eicosanoid biosynthesis - clinical consequences. Fett Wissenschaft Technologie 1994;95: Aldhous MC, Meister D, Subrata Ghosh, Ghosh S: Modification of enteral diets in inflammatory bowel disease. Symposium on Dietary influences on mucosal immunity, Harrogate, UK 2000; Alekseeva RI, Sharafetdinov Kh, Plotnikova OA, Meshcheriakova VA, Mal'tsev GI, Kulakova SN: Effects of diet therapy including eiconol on clinical and metabolic parameters in patients with type 2 diabetes mellitus. Voprosy Pitaniia 2000;69: Alfin -Slater RB, Aftergood L: Essential fatty acids reinvestigated. Physiological Reviews 1968;48: Anadere I, Schmitt Y, Schneider H, Walitza E: The effect of omega-3 polyunsaturated fatty acids on hemorheological parameters of patients under chronic hemodialysis treatment. Clinical Hemorheology 1992;12: Andersson Agneta: Fatty acid composition in skeletal muscle. Influence of physical activity and dietary fat quality. Dissertation Abstracts International 67- Astrup A: Healthy lifestyles in Europe: prevention of obesity and type II diabetes by diet and physical activity. Public Health Nutrition 2001;56: Aued Pimentel S, Caruso MSF: Gamma -linolenic acid: sources, and perspectives on its therapeutic application. Boletim da Sociedade Brasileira de Ciencia e Tecnologia de Alimentos 1999;54: Avula C, Lawrence R, Jolly C, Fernandes G: Role of n-3 polyunsaturated fatty acids (PUFA) in autoimmunity, inflammation, carcinogenesis, and apoptosis. Recent.Research.Developments.in.Lipids 2000; Ayling RM, Preedy VR, Grimble G, Watson R: Nutritional management of diabetes mellitus. Nutrition in the infant: problems and practical procedures 2001;36:- Ba Jaber AS, Al Faris NA: Effects of high carbohydrate, high insoluble fiber and low fatty acids diets on patients with non-insulin-dependent diabetes mellitus. Bulletin of Faculty of Agriculture, University of Cairo 1997;22: 73

91 Ba Jaber AS, Al Faris NA, Al Robean K: Short-term effect of soluble fiber in fat diets on plasma glucose and lipids in patients with non-insulin dependent diabetes mellitus. Bulletin of Faculty of Agriculture, University of Cairo 1997;25: Baggio B: Fatty acids, calcium and bone metabolism. Journal of Nephrology 2002;15: Bamba T: Lifestyle guidance and diet for inflammatory bowel disease (IBD) patients. JMAJ Japan Medical Association Journal 2002;4: Bang HO, Dyerberg J, Nielsen AB: Plasma lipid and lipoprotein pattern in Greenlandic West-coast Eskimos. Lancet 1971;1: Barsottelli E, Berra B: Omega-3 Fatty acids and prevention of thrombosis and atherosclerosis. Critical evaluation of data from the literature. Rivista Italiana delle Sostanza Grasse 1994;42: Bartels M, Nagel E, Pichlmayr R: What is the role of nutrition in ulcerative colitis? A contribution to the current status of diet therapy in treatment of inflammatory bowel diseases. Langenbecks Archiv fur Chirurgie 1995;380:37722 Bassaganya Riera J, Hontecillas R, Wannemuehler MJ: Nutritional impact of conjugated linoleic acid: a model functional food ingredient. In Vitro Cellular and Developmental Biology Plant 2002;50: Beare Rogers J, Nera EA, Levin OL, et al: 20th International Conference on the Biochemistry of Lipids, Aberdeen, Scotland, September 6-8, , xi + 44pp mimeographed.:- Beitz J, Schimke E, Liebaug U, et al: Influence of a cod liver oil diet in healthy and insulin-dependent diabetic volunteers on fatty acid pattern, inhibition of prostacyclin formation by low density lipoprotein (LDL) and platelet thromboxane. Klinische Wochenschrift 1986;64: Belch J, Muir A: n-6 and n-3 essential fatty acids in rheumatoid arthritis and other rheumatic conditions. Proceedings of the Nutrition Society 1998; Belluzzi A: Lipid treatment in inflammatory bowel disease. Nestle Nutrition Workshop Series Clinical & Performance Program 1999;2: Belluzzi A: N-3 and n-6 fatty acids for the treatment of autoimmune diseases. European Journal of Lipid Science and Technology 2001;6: Belluzzi A, Campieri M, Brignola C, Gionchetti P, Miglioli M, Barbara L: Polyunsaturated fatty acid pattern and fish oil treatment in inflammatory bowel disease. Gut 1993;34: Berdanier CD, Bodwell CE, Erdman JW: Interacting effects of carbohydrate and lipid on metabolism. Nutrient interactions 1988; Berry EM, Valagussa F, Marchioli R: Are diets high in omega-6 polyunsaturated fatty acids unhealthy? Evidence and perspectives on n 3 polyunsaturated fatty acids in cardiovascular disease. European- Heart-Journal-Supplements 2001; Betteridge DJ: Lipids, diabetes, and vascular dis ease: The time to act. Diabetic Medicine 1989;6: Bhathena SJ: Relationship between fatty acids and the endocrine system. Biofactors 2000;13: Bhathena SJ, Chow CK: Dietary fatty acids and fatty acid metabolism in diabetes. Fatty acids in foods and their health implications 2000;488:- Bisson LF, Watkins TR: Metabolic Syndrome X and the French paradox. Wine: nutritional and therapeutic benefits 1997;66:- Bitton A: Medical management of ulcerative proctitis, proctosigmoiditis, and left-sided colitis. Seminars in Gastrointestinal Disease 2001;12: Bodem SH: Is fish oil effective against IgAnephropathy? Pharmazeutische Zeitung 1995;140: Boissonneault G, Chow C: Dietary fat, immunity and inflammatory disease. Fatty.acids.in.foods.and.their.health.implications 2000;- Brennan GM, McVeigh GE, Johnston GD, Hayes JR: Dietary fish oil augments EDRF production or release in patients with non-insulin dependent diabetes mellitus. British Journal of Clinical Pharmacology 1992;33:531 74

92 Brown A: Lupus erythematosus and nutrition: a review of the literature. Journal of Renal Nutrition. 2000;10: Brunner EJ, Wunsch H, Marmot MG: What is an optimal diet? Relationship of macronutrient intake to obesity, glucose tolerance, lipoprotein cholesterol levels and the metabolic syndrome in the Whitehall II study. International Journal of Obesity 2001;30: Burakoff R: Inflammatory bowel disease workshop. Vail, Colorado, March 22 and 23, Less commonly used therapies for IBD or treatments on the fringe. Inflammatory Bowel Diseases 1998;4: Burden ML, Samanta A, Spalding D, Burden AC: A comparison of the glycaemic and insulinaemic effects of an Asian and a European meal. Practical Diabetes 1994;11: Campbell Joy Marlene: Influence of oligosaccharides and fish oil on gastrointestinal tract characteristics and metabolic profiles of humans, pigs, and rats. Dissertation Abstracts International Caprilli R, Taddei C, Viscido A: In favour of prophylactic treatment for post-operative recurrence in Crohn's disease. Italian Journal of Gastroenterology & Hepatology 1998;30: Carpentier YA: Dietary intake and hyperlipoproteinemias. Revue Medicale de Bruxelles 1997;18: Castiglioni A, Savazzi GM: Clinical significance of consumption of polyunsaturated n-3 fatty acids of marine origin. Recenti Progressi in Medicina 1991;82: Caterina R, de BG, De Caterina R, Valagussa F, Marchioli R: n-3 Fatty acids and the inflammatory response -biological background. Evidence and perspectives on n.3 polyunsaturated fatty acids in cardiovascular disease. European-Heart-Journal 2001; Caterina Rde Caprioli R, Giannessi D, Sicari R, et al: The use of fish oil in human chronic glomerular disease. n 3 fatty acids and vascular disease: background and pathophysiology, hyperlipidaemia, renal diseases, ischaemic heart disease 1993;51: Cerrato PL: Omega-3 fatty acids: nothing fishy here! RN 1999;62: Chambers Kathleen Mailie: Assessment of the nutritional properties of regular and low linolenic acid canola oil in non-insulin-dependent (Type ii) Diabetes mellitus subjects. Masters Abstracts International 519- Chandrasekaran A, Radhakrishna B, Uma B, Gopalan C, Krishnaswamy K: Rheumatic diseases. Nutrition.in.major.metabolic.diseases 2000;11:- Chaumerliac P, Pehuet-Figoni M, Escourolle H, Giauque JP, Luton JP: Lipid disorders in diabetes mellitus. Pathophysiology and therapeutic implications. I.- Physiologic review of the metabolism of VLDLs, HDLs and LDLs. Semaine des Hopitaux 1991;67: Chen SSC: Soybeans and health. Journal of the Chinese Nutrition Society 1994;19: Cheng IKP: Non-immune therapy of IgA glomerulonephritis. Nephrology 1997;3: Chowienczyk PJ, Watts GF: Endothelial dysfunction, insulin resistance and non-insulin-dependent diabetes. Endocrinology & Metabolism, Supplement 1997;4: Chutkan RK: Inflammatory bowel disease. Primary Care; Clinics in Office Practice 2001;28: Cimmino M: Regional differences in the occurrence and severity of rheumatoid arthritis in Europe. Cpd Rheumatology 1999;1: Clamp A: Investigations into the mechanisms by which fats modulate the inflammatory response to cytokines. Dissertation.Abstracts.International 56- Cleland LG, James MJ: Adulthood - prevention: Rheumatoid arthritis. Medical Journal of Australia 2002;176:S119-S120 Comas Maria: Patron plasmatico de los acidos grasos poliinsaturados en las diferentes fases evolutivas de la enfermedad inflamatori intestinal: Su relacion con factores clinicos, biologicos y nutricionales. Dissertation Abstracts International

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102 Schmitz PG, O' Donnell MP, Kasiske BL, Keane WF: Glomerular hemodynamic effects of dietary polyunsaturated fatty acid supplementation. Journal of Laboratory and Clinical Medicine 1991;43: Schwab D, Raithel M, Hahn EG: Enteral nutrition in acute Crohn disease. Zeitschrift fur Gastroenterologie 1998;36: Selby W: Current management of inflammatory bowel disease. Journal of Gastroenterology & Hepatology 1993;8: Seppanen R, Reunanen A: Diet habits of diabetics and nondiabetics in Finland. Naringsforskning 1979; Sharma RK, Sural S: Current management of glomerular diseases. Journal of Internal Medicine of India 1999;2: Shen Chwan Li: Effect of dietary polyunsaturated fatty acids on prostaglandin e(2) Aand insulin-like growth factor-i in bone modeling. Dissertation Abstracts International 56-09, Section: B:4663- Siamopoulou A, Challa A, Kapoglou P, Cholevas V, Mavridis A, Lapatsanis P: Effects of intranasal salmon calcitonin in juvenile idiopathic arthritis: An observational study. Calcified Tissue International 2001;69: Silvis N, Vorster HH, Mollentze WF, Jagar Jde Huisman HW, De Jager J: Metabolic and haemostatic consequences of dietary fibre and N-3 fatty acids in black type 2 (NIDDM) diabetic subjects: a placebo controlled study. International Clinical Nutrition Review 1990; Simonsen N: Nutritional Determinants of Rheumatoid Arthritis. Dissertation.Abstracts.International Simopoulos AP, Pavlou KN, Simopoulos AP, Pavlou KN: Nutrition and fitness 2: metabolic studies in health and disease 2001;- Simpser E, Daum F, Dinari G, et al: Nutrition in pediatric inflammatory bowel disease. Pediatric nutrition 1998;40:- Singer P, Gnauck G, Honigmann G, et al: The fatty acid pattern of adipose tissue and liver triglycerides according to fat droplet size in liver parenchymal cells of diabetic subjects. Diabetologia 1974; Singer P, Honigmann G, Schliack V: Decrease of eicosapentaenoic acid in fatty liver of diabetic subjects. Prostaglandins & Medicine 1980;5: Singer P, Honigmann G, Schliack V: On the fatty acids of the triglycerides in inflammatory liver diseases of diabetics without and with hyperlipoproteinemia. Zeitschrift fur die Gesamte Innere Medizin und Ihre Grenzgebiete 1981;36: Singh G: Fish oils in rheumatoid arthritis. Annals of Internal Medicine 1988;108: Singh RB, Rastogi SS, Rao PV, et al: Diet and lifestyle guidelines and desirable levels of risk factors for the prevention of diabetes and its vascular complications in Indians: a scientific statement of The International College of Nutrition. Indian Consensus Group for the Prevention of Diabetes. Journal of Cardiovascular Risk 1997;4: Sircar S, Kansra U: Choice of cooking oils --myths and realities. Journal of the Indian Medical Association 1998;96: Socha P, Ryzko J, Koletzko B, et al: The influence of fish oil therapy in children with inflammatory bowel disease on the fatty acid status. Pediatria Wspolczesna 2002;4: Song T: Soy isoflavones: Database development, estrogenic activity of glycitein and hypocholesterolemic effect of daidzein. Dissertation Abstracts International 59:5638- Sorokin EL, Smoliakova GP, Bachaldin IL: Clinical efficacy of eiconol in patients with diabetic retinopathy. Vestnik Oftalmologii 1997;113: Soustre Y, Laurent B, Schrezenmeir J, Pfeuffer M, Miller G, Parodi P: Trans fatty acids. Bulletin of the International Dairy Federation 2002;- Stender S, Jensen T, Deckert T: Experience with fish oil treatment with special emphasis on diabetic nephropathy. Journal of Diabetic Complications 1990;4: Stone NJ, Van Horn L: - Therapeutic Lifestyle Change and Adult Treatment Panel III: Evidence Then and Now. Current Atherosclerosis Reports 2002;4:

103 Stotland BR, Lichtenstein GR: Newer treatments for inflammatory bowel disease. Primary Care; Clinics in Office Practice 1996;23: Stotland BR, Lichtenstein GR: Newer treatments for inflammatory bowel disease. Drugs of Today 1998;34: Sugano M, Ikeda A: Regulation of soybean protein of alpha-linolenic acid metabolism: effect of diabetes. Report of the Soy Protein Research Committee Japan 1995;6 ref.: Takazakura E, Ohsawa K, Hamamatsu K, et al: Prevention and treatment of diabetic nephropathy; Decreased microalbuminuria after six months treatment with eicosapentaenoic acid (EPA) ethyl ester. Conference: The Third International Symposium on treatment of Diabetes Mellitus 13 JUL 1988 to 15 JUL 1988; Nagoya, JAPAN 1990; Tamas D, Gyorgyi C, Katalin T, et al: Polyunsaturated fatty acids in plasma lipids of obese children with and without metabolic cardiovascular syndrome. Lipids 2000; Tjornum TE: Olive oil for patients with diabetes. Ugeskrift for Laeger 1995;157: Tjornum TE: Olive oil to diabetics--again. Ugeskrift for Laeger 1995;157:3637- Tobin A: Fish oil supplementation and ulcerative colitis. Annals of Internal Medicine 1992;117: Toeller M: Nutritional therapy in diabetes mellitus. Aktuelle Ernahrungsmedizin 2002;27 : Tonstad S: Drug therapy of hyperlipidemia -- unanswered questions. Tidsskrift for Den Norske Laegeforening 1997;117: Tonstad S: Indications for lipid-lowering drugs: Unanswered questions. Tidsskrift for Den Norske Laegeforening 1997;117: Tonstad S, Leren TP, Ose L: Diagnosis and treatment of severe hyperlipidemia. Tidsskrift for Den Norske Laegeforening 1997;117: Turpin G, Bruckert E: Management of atherogenic hyperlipidemia. Annales de Cardiologie et d Angeiologie 1998;47: Uauy R, Mena P, Valenzuela A: Essential fatty acids as determinants of lipid requirements in infants, children and adults. European Journal of Clinical Nutrition 1999;53:S 7 Ueki M, Matsui T, Yamada M, et al: Randomized controlled trial of amino acid based diet versus oligopeptide based diet in enteral nutritional therapy of active Crohn's disease. Japanese Journal of Gastroenterology 1994;91: Uhlig T: Clinical application of omega 3 fatty acids (fish oil). Deutsche Medizinische Wochenschrift 1995;120: Uusitupa M, Louheranta A, Lindstrom J, et al: The Finnish Diabetes Prevention Study. Diet and the metabolic syndrome Valensi P, Attalah M, Behar A, Attali JR: Capillary permeability in diabetes. [French]. Sang Thrombose Vaisseaux 1994;6: Valtuena S, Sette S, Branca F: Influence of Mediterranean diet and Mediterranean lifestyle on calcium and bone metabolism. International Journal for Vitamin & Nutrition Research. 2001;71: Vanbeber Anne Duffy: The effect of omega-3, omega-6, and omega-9 fatty acid supplements on the serum fatty acid profile and immune response of renal dialysis patients (Fish oil). Dissertation Abstracts International Vaupel N: Substitution of Omega-3 fatty acids in type I and type II diabetics. Fortschritte der Medizin 1996;114:32- Venter CS, van Eyssen E: More legumes for better overall health. SAJCN South African Journal of Clinical Nutrition 2001;S32-3. Vergroesen AJ, Crawford M: Role of fats in human nutrition. 2002;Hardback.:- Vessby B: Dietary fat and insulin action in humans. British Journal of Nutrition 2000;83:S6 86

104 Voigt J, Hagemeister H: Dietary influence on a desirable fatty acid composition in milk from dairy cattle. New trends in animal nutrition, June, 2001, Jachranka, Poland 2001; Volkert R: Omega 3 fatty acids: Fish oil capsules as drugs. Zeitschrift fur Allgemeinmedizin 1990;66:776- Von Ritter C: Inflammatory bowel disease. Pathophysiology and medical treatment. Radiologe 1998;38:3-7. Wahlqvist ML, Lo CS, Myers KA: Fish intake and arterial wall characteristics in healthy people and diabetic patients. Lancet 1989;2: Wahlqvist ML, Lo CS, Myers KA: Relationships between fish intake and arterial wall characteristics. Proceedings of the Nutrition Society of Australia 1988;3 ref.:1013- Wahrburg U: Mediterranean diet and its role in the prevention and treatment of diet-related diseases. Internistische Praxis 2001;41: Wardle EN: Alternative therapies for vasculitis and proliferative nephritides: The role of cyclic AMP elevating agents. Renal Failure 1998;20:7-13. Wardle EN: IgA nephropathy. New England Journal of Medicine Online 2003;348: Wardle EN: Rationales for treating IgA nephropathies. Renal Failure 2000;22:1-16. Watkins B, Seifert M: Conjugated linoleic acid and bone biology. Journal of the American College of Nutrition 2000;478S-486S. Watson J, Madhok R, Wijelath E, et al: Mechanism of action of polyunsaturated fatty acids in rheumatoid arthritis. Biochemical.Society Transactions. 1990; Weber N: Oleic acid-rich fats in nutrition. Schriftenreihe des Bundesministeriums fur Ernahrung, Landwirtschaft und Forsten 1997;- Wijendran Vasuki: Long chain polyunsaturated fatty acid metabolism in normal pregnancy and pregnancy complicated with gestational diabetes mellitus. Dissertation Abstracts International Wilhelmi G: Potential effects of nutrition including additives on healthy and arthrotic joints. I. Basic dietary constituents. Zeitschrift fur Rheumatologie 1993;52: Wolfram G: Diet therapy in metabolic diseases years of rational dietetics in Germenay ; Wolfram G: Omega3- and omega6-fatty acids - biochemical specialities and biological effects. Fett Wissenschaft Technologie 1989; Woo J, Ho SC, Yu AL: Lifestyle factors and health outcomes in elderly Hong Kong chinese aged 70 years and over. Gerontology 2002;48: Wright J, Furst P: Effect of high-carbohydrate versus high-monounsaturated fatty acid diet on metabolic control in diabetes and hyperglycemic patients. Consensus roundtable on nutrition support of tube fed patients with diabetes Yam D, Friedman J, Bott-Kanner G, Genin I, Shinitzky M, Klainman E: Omega-3 fatty acids reduce hyperlipidaemia, hyperinsulinaemia and hypertension in cardiovascular patients. Journal of Clinical & Basic Cardiology 2002;5: Yamamoto S: Essential unsaturated fatty acids. Nippon Rinsho - Japanese Journal of Clinical Medicine 1999;57: Yeh Lan Lan Liang: The relationship of serum fatty acid distributions to the risk of coronary heart disease and dietary intake (Fatty acids). Dissertation Abstracts International Yszko JS, Yszko J, Pawlak K, liwiec M: Effect of treating glomerulonephritis with omega 3 fatty acids for selected parameters of hemostasis, blood platelet function and lipid metabolism. Przeglad Lekarski 1996;53: Yurawecz MP, Mossoba MM, Kramer JKG, Pariza MW, Nelson GJ: Advances in conjugated linoleic acid research, volume ;- Zaccagna CA, Zullo G: The erectile dysfunction. Alimentary approach by metabolic supplementation with PUFA - 3. Gazzetta Medica Italiana 2002;161:

105 Zak A, Zeman M, Tvrzicka E, et al: Glucose tolerance, insulin secretion, plasma lipid fatty acids, and the hypolipidemic effects of fish oil. Dietary lipids and insulin action Second International Smolenice Insulin Symposium Zeman M, Zak A, Tvrzicka E, Buchtikova M, Stipek S, Pousek L: [Insulinemia, fatty acids in plasma lipids and lipoproteins and oxidation of VLDL and LDL in hyperlipidemia. Sbornik Lekarsky 2000;101: Zurier R, Rossetti R, Furse R, Huang Y, Ziboh V: Gamma -Linolenic acid, inflammatory arthritis, and immune responses. Gamma.Linolenic.acid:.recent.advances.in.biotechno logy.and.clinical.applications. 2001;38:- 88

106 Rejected RAND's Search Unsuccessful Adam O: The role of dietary fat] in the prevention and therapy of nutrition-related diseases: the point of view of a rheumatologist. 7th Aachen dietetic continuing education 6: Castiglioni A, Savazzi GM: The prevention and treatment of diabetic nephropathy. European Journal of Internal Medicine 1993;4: Corda Christophe: Contribution a l'etude du role des acides gras polyinsatures de la serie omega-3 dans la prevention de la nephrotoxicite de la ciclosporine a chez des patients ayant beneficie d'une greffe de rein: Etude randomisee en double aveugle contre placebo. Dissertation Abstracts International 53: 693- Donnellan Christopher Edward: The effect of different dietary fatty acids upon the development of obesity and insulin resistance. Dissertation Abstracts International 61-04:1023- Heller A, Koch T: Omega-3 fatty acids as adjuvant therapy in inflammatory diseases. Anaesth Intensivmedizin 1996;10: Lau C, Morley K, McMahon H, Belch J: Maxepa reduced non-steroidal anti-inflamatory drug requirement in patients with mild rheumatoid arthritis. Hung Rheumatol 1991;32:126a Lee T, Austen K: Arachidonic acid metabolism by the 5-lipoxygenase pathway, and the effects of alternative dietary fatty acids. Advances in Immunology 1986;39: Tulleken J: Long chain omega-3 polyunsaturated fatty acids in rheumatoid arthritis. The Netherlands. Rijksuniversiteit Groningen 1991; 89

107 Rejected Condition Abate N, Jialal I: Therapy and clinical trials. Current Opinion in Lipidology 2002;13: Adam O: Nutrition as adjuvant therapy for chronic polyarthritis. Zeitschrift fur Rheumatologie 1993;52: Adam O, Schubert A, Adam A, Antretter N, Forth W: Effects of omega-3 fatty acids on renal function and electrolyte excretion in aged persons. European Journal of Medical Research 1998; 3: Almallah YZ, El Tahir A, Heys SD, Richardson S, Eremin O: Distal procto-colitis and n-3 polyunsaturated fatty acids: the mechanism(s) of natural cytotoxicity inhibition. European Journal of Clinical Investigation 2000;30: Arrington JL, McMurray DN, Switzer KC, Fan YY, Chapkin RS: Docosahexaenoic acid suppresses function of the CD28 costimulatory membrane receptor in primary murine and Jurkat T cells. Journal of Nutrition 2001;131: Assmann G, Backer Gde Bagnara S, Betteridge J, et al: International consensus statement on olive oil and the Mediterranean diet: implications for health in Europe. European Journal of Cancer Prevention 1997;30: Baird D, Umbach D, Lansdell L, et al: Dietary intervention study to assess estrogenicity of dietary soy among postmenopausal women. J Clin Endocrinol Metab 1995;80: Baker PW, Gibbons GF: Effect of dietary fish oil on the sensitivity of hepatic lipid metabolism to regulation by insulin. Journal of Lipid Research 2000;48: Barham JB, Edens MB, Fonteh AN, Johnson MM, Easter L, Chilton FH: Addition of eicosapentaenoic acid to gamma-linolenic acid-supplemented diets prevents serum arachidonic acid accumulation in humans. Journal of Nutrition 2000;130: Berlin E, Bhathena SJ, Judd JT, et al: Effects of omega-3 fatty acid and vitamin E supplementation on erythrocyte membrane fluidity, tocopherols, insulin binding, and lipid composition in adult men. Journal of Nutritional Biochemistry 1992;3: Bhathena SJ, Berlin E, Judd JT, et al: Effects of omega 3 fatty acids and vitamin E on hormones involved in carbohydrate and lipid metabolism in men. American Journal of Clinical Nutrition 1991;54: Bordin P, Bodamer OA, Venkatesan S, Gray RM, Bannister PA, Halliday D: Effects of fish oil supplementation on apolipoprotein B100 production and lipoprotein metabolism in normolipidaemic males. European Journal of Clinical Nutrition 1998;52: Borkman M, Storlien LH, Pan DA, Jenkins AB, Chisholm DJ, Campbell LV: The relation between insulin sensitivity and the fatty-acid composition of skeletal-muscle phospholipids. New England Journal of Medicine 1993;42 :4 Bourre JM, Dumont O, Piciotti M, et al: Essentiality of omega-3 fatty acids for brain structure and function, in Simopoulos AP, Kifer RR, Martin RE, Barlow SM (eds): Health effects of omega-3 polyunsaturated fatty acids in seafoods. Basel, Karger, World Rev Nutr Diet; 1991: Broadhurst CL: Balanced intakes of natural triglycerides for optimum nutrition: an evolutionary and phytochemical perspective. Medical Hypotheses 1997;49: Brooks Angela Todd: The influence of ground flaxseed or flaxseed oil on indicators for diabetes in adults. Masters Abstracts International 40-05: Brzezinski A, Adlercreutz: Short term effects of phytoestrogen-rich diet on postmenopausal women. Menopause 1997;4: Burn JH: Early observations and their importance today. I. Diabetes in childhood, II. Theophylline in myasthenia gravis, III. Properties of cod liver oil. Journal of Pharmacy & Pharmacology 1978;30: Burnett JR, Watts GF: Therapeutic considerations for postprandial dyslipidaemia. Diabetes, Obesity & Metabolism 2001;3:

108 Campbell JM, Fahey GC, Demichele SJ, Garleb KA: Metabolic characteristics of healthy adult males as affected by ingestion of a liquid nutritional formula containing fish oil, oligosaccharides, gum arabic and antioxidant vitamins. Food & Chemical Toxicology 1997;35: Campos FG, Waitzberg DL, Habr Gama A, et al: Impact of parenteral n -3 fatty acids on experimental acute colitis. British Journal of Nutrition 2002;87:S83-S88 Candela M, Cherubini G, Chelli F, Danieli G, Gabrielli A: Fish-oil fatty acid supplementation in mixed cryoglobulinemia: a preliminary report. Clinical & Experimental Rheumatology 1994;12: Carroll DN, Roth MT: Evidence for the cardioprotective effects of omega-3 fatty acids. Annals of Pharmacotherapy 2002;36: Caughey GE, Mantzioris E, Gibson RA, Cleland LG, James MJ: The effect on human tumor necrosis factor alpha and interleukin 1beta production of diets enriched in n-3 fatty acids from vegetable oil or fish oil. American Journal of Clinical Nutrition 1996;63: Chan DC, Watts GF, Barrett PH, Beilin LJ, Mori TA: Effect of atorvastatin and fish oil on plasma highsensitivity C-reactive protein concentrations in individuals with visceral obesity. Clinical Chemistry 2002;48: Clarke SD: Polyunsaturated fatty acid regulation of gene transcription: a molecular mechanism to improve the metabolic syndrome. Journal of Nutrition 2001;131: Clarke SD, Baillie R, Jump DB, Nakamura MT: Fatty acid regulation of gene expression. Its role in fuel partitioning and insulin resistance. Annals of the New York Academy of Sciences 1997;827: Cleland L, James M, Neumann M, D'Angelo M, Gibson R: Linoleate inhibits EPA incorporation from dietary fish-oil supplements in human subjects. Am J Clin Nutr 1992;55: Craig WJ: Phytochemicals: guardians of our health. Journal of the American Dietetic Association 1997;97:Suppl-204 Dagnelie PC, Rietveld T, Swart GR, Stijnen T, van den Berg JW: Effect of dietary fish oil on blood levels of free fatty acids, ketone bodies and triacylglycerol in humans. Lipids 1994;29: Dam RM van Willett WC, Rimm EB, Stampfer MJ, Hu FB, van Dam RM: Dietary fat and meat intake in relation to risk of type 2 diabetes in men. Diabetes Care 2002;25: Das UN: GLUT-4, tumor necrosis factor, essential fatty acids and daf-genes and their role in insulin resistance and non-insulin dependent diabetes mellitus. Prostaglandins Leukotrienes & Essential Fatty Acids 1999;60: Davey G: - Randomised controlled trial of a 12-week exercise intervention and omega-3 fatty acids in improving insulin sensitivity among South Asians and Europeans. - Clinical Science 1997;Vol.93:25P de Lorenzo A, Petroni ML, Luca PP de Andreoli A, et al: Use of quality control indices in moderately hypocaloric Mediterranean diet for treatment of obesity. Diabetes, Nutrition and Metabolism 2001;14: Delarue J, Couet C, Cohen R, Brechot JF, Antoine JM, Lamisse F: Effects of fish oil on metabolic responses to oral fructose and glucose loads in healthy humans. American Journal of Physiology - Endocrinology & Metabolism 1996;270:E353-E362 DeMarco D, Santoli D, Zurier R: Effects of fatty acids on proliferation and activation of human synovial compartment lymphocytes. Journal of Leukocyte Biology 1994;56: Denke MA: Dietary prescriptions to control dyslipidemias. Circulation 2002;105: DiGiacomo R, Kremer J, Shah D: Fish-oil dietary supplementation in patients with Raynauds phenomenom: A double-blind, controlled, prospective study. Am J Med 1989;86: Dolecek TA, Grandits G: Dietary polyunsaturated fatty acids and mortality in the Multiple Risk Factor Intervention Trial (MRFIT), in Simopoulos AP, Kifer RR, Martin RE, Barlow SM (eds): Health effects of omega-3 polyunsaturated fatty acids in seafoods. Basel, Karger, World Rev Nutr Diet; 1991:

109 Dubois C, Cara L, Armand M, et al: Effects of pea and soybean fibre on postprandial lipaemia and lipoproteins in healthy adults. European Journal of Clinical Nutrition 1993;47: Durrington PN, Bhatnagar D, Mackness MI, et al: An omega-3 polyunsaturated fatty acid concentrate administered for one year decreased triglycerides in simvastatin treated patients with coronary heart disease and persisting hypertriglyceridaemia. Heart (British Cardiac Society) 2001;85: Ekblond A, Mellemkjaer L, Tjonneland A, et al: A cross-sectional study of dietary habits and urinary glucose excretion - a predictor of non-insulindependent diabetes mellitus. European Journal of Clinical Nutrition 2000;54: Emeis JJ, van Houwelingen AC, van den Hoogen CM, Hornstra G: A moderate fish intake increases plasminogen activator inhibitor type-1 in human volunteers. Blood 1989;74: Endres S, Ghorbani R, Kelley V, et al: The effect of dietary supplementation with n-3 polyunsaturated fatty acids on the synthesis of interleukin-1 and tumor necrosis factor by mononuclear cells. N Engl J Med 1989;320: Fisher WR: Hypertriglyceridemia in diabetes. An approach to management. Journal of the Florida Medical Association 1991;78: Franceschini G, Paoletti R: Pharmacological management of hypertriglyceridemic patients. Cardiovascular Risk Factors 1992;2: Friedberg CE, Janssen MJ, Heine RJ, Grobbee DE: Fish oil and glycemic control in diabetes. A metaanalysis. Diabetes Care 1998;21: Ginsberg HN, Illingworth DR: Postprandial dyslipidemia: an atherogenic disorder common in patients with diabetes mellitus. American Journal of Cardiology 2001;88:9H-15H. Gletsu NA, Clandinin MT: Impact of dietary fatty acid composition on insulin action at the nucleus. Annals of the New York Academy of Sciences 1997;827: Gohlke H: Diet and body weight. Zeitschrift fur Kardiologie 2002;91: Goulet O, de Potter S, Antebi H, et al: Long-term efficacy and safety of a new olive oil-based intravenous fat emulsion in pediatric patients: a double-blind randomized study. American Journal of Clinical Nutrition 1999;70: Grimb le R, Tappia P: Modulation of proinflammatory cytokine biology by unsaturated fatty acids. Zeitschrift fur Ernahrungswissenschaft. 1998;37: Grundt H, Nilsen DW, Hetland O, et al: Improvement of serum lipids and blood pressure during intervention with n-3 fatty acids was not associated with changes in insulin levels in subjects with combined hyperlipidaemia. Journal of Internal Medicine 1995;237: Guarner F, Vilaseca J, Malagelada JR: Dietary manipulation in experimental inflammatory bowel disease. Agents & Actions 1992;35:C10-C14 Gustafsson I-B, Ohrvall M, Ekstrand B, Vessby B: Moderate amounts of n-3 fatty acid enriched seafood products are effective in lowering serum triglycerides and blood pressure in healthy subjects. Journal of Human Nutrition & Dietetics 1996;9: Haglund O, Wallin R, Wretling S, Hultberg B, Saldeen T: Effects of fish oil alone and combined with long chain (n-6) fatty acids on some coronary risk factors in male subjects. Journal of Nutritional Biochemistry 1998;9: Hall AV, Parbtani A, Clark WF, et al: Abrogation of MRL/lpr lupus nephritis by dietary flaxseed. American Journal of Kidney Diseases 1993;22: Harding WR, Russell CE, Davidson F, Prior IAM: Dietary surveys from the Tokelau Island Migrant Study. Ecology of Food and Nutrition 1986;19: Healy DA, Wallace FA, Miles EA, Calder PC, Newsholme P: Effect of low-to-moderate amounts of dietary fish oil on neutrophil lipid composition and function. Lipids 2000;35: Henderson WR: Omega-3 supplementation in CF. 6th North American Cystic Fibrosis Conference 1992;- 92

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129 Vassilopoulos D, Zurier R, Rossetti R, Tsokos G: Gammalinolenic acid and dihomogammalinolenic acid suppress the CD3mediated signal transduction pathway in human T cells. Clinical Immunology & Immunopathology 1997;83: Vazquez IM, Millen B, Bissett L, Levenson SM, Chipkin SR: Buena Alimentacion, Buena Salud: A preventive nutrition intervention in Caribbean Latinos with type 2 diabetes. American Journal of Health Promotion 1998;13: Vessby B, Aro A, Skarfors E, Berglund L, Salminen I, Lithell H: The risk to develop NIDDM is related to the fatty acid composition of the serum cholesterol esters. Diabetes 1994;43: Vessby B, Unsitupa M, Hermansen K, et al: Substituting dietary saturated for monounsaturated fat impairs insulin sensitivity in healthy men and women: The KANWU Study. Diabetologia 2001;44: Wahrburg U, Kratz M, Cullen P: Mediterranean diet, olive oil and health. European Journal of Lipid Science and Technology 2002;104: Walker KZ, O' Dea K: Is a low fat diet the optimal way to cut energy intake over the long term in overweight people? Nutrition Metabolism and Cardiovascular Diseases 2001; Walker KZ, O'Dea K, Nicholson GC, Muir JG: Dietary composition, body weight, and NIDDM: Comparison of high-fiber, high-carbohydrate, and modified-fat diets. Diabetes Care 1995;18: Wallace AJ, Sutherland WHF, Mann JI, Williams SM: The effect of meals rich in thermally stressed olive and safflower oils on postprandial serum paraoxonase activity in patients with diabetes. European Journal of Clinical Nutrition 2001;55: Wallace DJ: Systemic lupus erythematosus and Sjogren's syndrome. Current Opinion in Rheumatology 1994;6: Watson J, Byars ML, McGill P, Kelman AW: Cytokine and prostaglandin production by monocytes of volunteers and rheumatoid arthritis patients treated with dietary supplements of blackcurrant seed oil. British Journal of Rheumatology 1993;32: Watts GF: Coronary disease, dyslipidaemia and clinical trials in type 2 diabetes mellitus. Practical Diabetes International 2000;17: Welch IM, Bruce C, Hill SE, Read NW: Duodenal and ileal lipid suppresses postprandial blood glucose and insulin responses in man: possible implications for the dietary management of diabetes mellitus. Clinical Science 1987;72: West KM: Diet therapy of diabetes: an analysis of failure. Annals of Internal Medicine 1973;79: Williams DEM, Prevost AT, Whichelow MJ, Cox BD, Day NE, Wareham NJ: A cross-sectional study of dietary patterns with glucose intolerance and other features of the metabolic syndrome. British Journal of Nutrition 2000;83: Williams WV, Rosenbaum H, Zurier RB: Effects of unsaturated fatty acids on expression of early response genes in human T lymphocytes. Pathobiology 1996;64: Wing RR, Marcus MD, Salata R, Epstein LH, Miaskiewicz S, Elaine HB: Effects of a very-lowcalorie diet on long-term glycemic control in obese type 2 diabetic subjects. Archives of Internal Medicine 1991;151 : Wolever TMS, Mehling C: High-carbohydrate-lowglycaemic index dietary advice improves glucose disposition index in subjects with impaired glucose tolerance. British Journal of Nutrition 2002;87: Wuesten O, Balz CH, Kloer HU, Bretzel RG, Linn T: Enhancement of beta-cell sensitivity to glucose by oral fat load. Hormone & Metabolic Research 2001;33: Wyatt RJ, Hogg RJ: Evidence-based assessment of treatment options for children with IgA nephropathies. Pediatric Nephrology 2001;16: Yamamoto K, Asakawa H, Tokunaga K, et al: Longterm ingestion of dietary diacylglycerol lowers serum triacylglycerol in type II diabetic patients with hypertriglyceridemia. Journal of Nutrition 2001;131:

130 Yaqoob P, Knapper JA, Webb DH, Williams CM, Newsholme EA, Calder PC: Effect of olive oil on immune function in middle-aged men. American Journal of Clinical Nutrition 1998;67: Young TK, Gerrard JM, O'Neil JD: Plasma phospholipid fatty acids in the central Canadian arctic: biocultural explanations for ethnic differences. American Journal of Physical Anthropology 1999;109:9-18. Zock PL, Mensink RP, Harryvan J, De Vries JHM, Katan MB: Fatty acids in serum cholesteryl esters as quantitative biomarkers of dietary intake in humans. American Journal of Epidemiology 1997;145:

131 Rejected Population Bonnema SJ, Jespersen LT, Marving J, Gregersen G: Supplementation with olive oil rather than fish oil increases small arterial compliance in diabetic patients. Diabetes, Nutrition & Metabolism - Clinical & Experimental 1995;8: Cameron NE, Cotter MA: Effects of antioxidants on nerve and vascular dysfunction in experimental diabetes. Diabetes Research & Clinical Practice 1999;45: Cathcart E, Gonnerman WA: Fish oil fatty acids and experimental arthritis. Rheum Dis Clin North Am 1991;17: Clandinin MT, Cheema S, Field CJ, Baracos VE: Dietary lipids influence insulin action. Annals of the New York Academy of Sciences 1993;683: Edrees GMF, Othman AB, Amer MA: Influence of zinc supplementation and soybean feeding in controlling some diabetic disorders. Egyptian Journal of Food Science 1991;20 ref.:1-2, 217. Field CJ, Goruk SD, Wierzbicki AA, Clandinin MT: The effect of dietary fat content and composition on adipocyte lipids in normal and diabetic states. International Journal of Obesity 1989;13: Gerbi A, Maixent JM, Barbey O, et al: Neuroprotective effect of fish oil in diabetic neuropathy. Lipids 1999;7: Haines AP, Sanders TA, Imeson JD, et al: Effects of a fish oil supplement on platelet function, haemostatic variables and albuminuria in insulindependent diabetics. Thrombosis Research 1986;43: Lungershausen YK, Howe PRC, Clifton PM, et al: Evaluation of an omega-3 fatty acid supplement in diabetics with microalbuminuria. Annals of the New York Academy of Sciences 1997;827: Mori TA, Vandongen R, Masarei JR, Rouse IL, Dunbar D: Comparison of diets supplemented with fish oil or olive oil on plasma lipoproteins in insulindependent diabetics. Metabolism: Clinical & Experimental 1991;40: Ogborn MR, Nitschmann E, Bankovic -Calic N, Weiler HA, Aukema H: Dietary flax oil reduces renal injury, oxidized LDL content, and tissue n-6/n-3 FA ratio in experimental polycystic kidney disease. Lipids 2002;37: Ohtake T, Kimura M, Takemura H, Hishida A: Effects of dietary lipids on daunomycin-induced nephropathy in mice: comparison between cod liver oil and soybean oil. Lipids 2002;4: Reifen R: Nutrition and autoimmunity. Israel Journal of Medical Sciences 1997;33: Robinson DR, Knoell CT, Urakaze M, et al: Suppression of autoimmune disease by omega-3 fatty acids. Biochemical Society Transactions 1995;23: Robinson DXL, Tateno S, Guo M, Colvin R: Suppression of autoimmune disease by dietary n-3 fatty acids. Journal of Lipid Research 1993;34: Shohat J, Boner G: Role of lipids in the progression of renal disease in chronic renal failure: evidence from animal studies and pathogenesis. Israel Journal of Medical Sciences 1993;29: Stiefel P, Ruiz-Gutierrez V, Gajon E, et al: Sodium transport kinetics, cell membrane lipid composition, neural conduction and metabolic control in type 1 diabetic patients. Changes after a low-dose n-3 fatty acid dietary intervention. Annals of Nutrition & Metabolism 1999;43: Tariq T, Close C, Dodds R, Viberti GC, Lee T, Vergani D: The effect of fish-oil on the remission of type 1 (insulin -dependent) diabetes in newly diagnosed patients. Diabetologia 1989;32:765- Thaiss F, Schoeppe W, Germann P, Stahl RAK: Dietary fish oil intake: effects on glomerular prostanoid formation, hemodynamics, and proteinuria in nephrotoxic serum nephritis. Journal of Laboratory and Clinical Medicine 1990;33 ref.: Watkins B, Lippman H, Le Bouteiller L, Li Y, Seifert M: Bioactive fatty acids: role in bone biology and bone cell function. Progress in Lipid Research. 2001;40:

132 Weise WJ, Natori Y, Levine JS, et al: Fish oil has protective and therapeutic effects on proteinuria in passive Heymann nephritis. Kidney International 1993;48: Yagasaki K: Evaluation of therapeutic potential of dietary manipulations and food factors against nephritis and cancer by in vivo and in vitro disease models. Nippon Eiyo Shokuryo Gakkaishi = Journal of the Japanese Society of Nutrition and Food Science 2000;45: 115

133 Rejected Study Design Descriptive AnonymousII. International conference on the health effects of omega-3 polyunsaturated fatty acids in seafoods. Zeitschrift fur Arztliche Fortbildung 1991;85:196- AnonymousInflammatory bowel diseases. Medecine et Chirurgie Digestives 1991;20: AnonymousSomething fishy for them joints? Hospitals & Health Networks 1995;69:12- American Diabetes Association: Evidence-based nutrition principles and recommendations for the treatment and prevention of diabetes and related complications. Journal of the American Dietetic Association 2002;7: Ballou SP: Systemic lupus erythematosus. Controversies in management. Postgraduate Medicine 1987;81: Barth C: Prognostic risk factors as an indication for the early treatment of IgA nephritis. Deutsche Medizinische Wochenschrift 2000;125:1009- Benedek T: Treatment of systemic lupus erythematosus: from cod-liver oil to cyclosporin. Lancet. 1998;352: Cotton P: New approaches may aid patients with inflammatory bowel disease. JAMA 1990;263: Daniel H, Metzger B: The pathogenesis and therapy of chronic inflammatory bowel diseases. Deutsche Apotheker Zeitung 1990;130: Das UN: Insulin resistance and hyperinsulinaemia: Are they secondary to an alteration in the metabolism of essential fatty acids? Medical Science Research 1994;22: Donadio JV, Bergstralh EJ, Offord KP, Holley KE, Spencer DC: Clinical and histopathologic associations with impaired renal function in IgA nephropathy. Mayo Nephrology Collaborative Group. Clinical Nephrology 1994;41: Ernst E: Complementary/alternative medicine in rheumatology-between negligence, ignorance and arrogance. Osteoarthritis & Cartilage 2002;10: Funk C: Current drug therapy of colitis. Ars Medici 1990;80: Gassull MA: Polyunsaturated fatty acids in inflammatory bowel diseases. Pediatrika 1997;17: Harrison R, Harrison B, Volker D, Garg M: Fish oils are beneficial to patients with established rheumatoid arthritis. Journal of Rheumatology 2001;28: Hart F, Karmali R, Birtwistle S, McEwen L: Dietary fatty acids and rheumatoid arthritis. Lancet 1985;1: Hogg RJ: A randomized, placebo-controlled, multicenter trial evaluating alternate-day prednisone and fish oil supplements in young patients with immunoglobulin A nephropathy. American Journal of Kidney Diseases 1995;26: Howard WJ: Is it time for a clinical trial of dietary fish oil supplementation in individuals with NIDDM? Annals of the New York Academy of Sciences 1993;683: Korelitz BI, Stenson WF, Cort D, et al: Fish oil supplementation in ulcerative colitis. Deutsche Medizinische Wochenschrift 1993;118:925- Kremer J: Omega-3 fatty acids in rheumatoid arthritis. Delaware.Medical Journal 1988: Kromhout Dand Feskens EJ: Nutrition and diabetes: the role of fat. Acta Cardiologica 1993;48: Lauritzen K, Fabech B, Bager S, Larsen C: Fish oil. Ugeskrift for Laeger 2002;164: Lorenz-Meyer H, Purrmann J, Scheurlen C, et al: Ergebnisse der Studie zur Erhaltung der Remission bei Morbus Crohn mit o-3 FS bzw. einer kohlenhydratarmen Kost. Z Gastroenterol 1992;30:654 Luostarinen R, Wallin R, Wibell L, Saldeen T: Vitamin E supplementation counteracts the fish oilinduced increase of blood glucose in humans. Nutrition Research 1995;15:

134 Petrie KJ, Cundy T: Alternative medicine recommendations to patients with Type 2 diabetes visiting health product shops and pharmacies. Diabetic Medicine 2002;19:1035- Shanahan F, Targan S: Medical treatment of inflammatory bowel disease. Annual Review of Medicine 1992;43: Siguel E: Low- and high-fat, peptide-based diets in adolescents with active Crohn's disease. Journal of Parenteral & Enteral Nutrition 1997;21:304- Singer P: Third International Congress on Essential Fatty Acids and Eicosanoids. Aktuelle Ernahrungsmedizin Klinik und Praxis 1992;17: Stotland BR, Cirigliano MD, Lchtenstein GR: Medical therapies for inflammatory bowel disease. Hospital Practice 1998;33:

135 Rejected Study Design Review/Meta-Analysis Anonymous Fish oil. Alternative Medicine Review 2000;5: Anonymous Fish oil supplements. Geneesmiddelenbulletin 1999;33: Anonymous Fish oils in rheumatoid arthritis. Lancet 1987;2: Anonymous Minerva. BMJ 1996;312:322- Anonymous Nonspecific immunosuppressive therapies still the mainstay for SLE. Drugs & Therapy Perspectives 1996;8:5-9. Adam O: Anti-inflammatory diet in rheumatic diseases. European Journal of Clinical Nutrition 1995;49: Adam O: Nutrition and immun system: Rheumatism. Aktuelle Ernahrungsmedizin 2002;27: Alarcon de la Lastra Barranco M, Motilva V, Herrerias J: Mediterranean diet and health: Biological importance of olive oil. Current Pharmaceutical Design 2001;7: Albertazzi P, Coupland K: Polyunsaturated fatty acids. Is there a role in postmenopausal osteoporosis prevention? Maturitas. 2002;42: Alexander J: Immunonutrition: The role of omega-3 fatty acids. Nutrition 1998;14: Anderson JW, Smith BM, Washnock CS: Cardiovascular and renal benefits of dry bean and soybean intake. American Journal of Clinical Nutrition 1999;70:464S-474S. Andreani D, Di Mario U, Pozzilli P: Prediction, prevention, and early intervention in insulindependent diabetes. Diabetes-Metabolism Reviews 1991;7: Angelin B, Palmblad J: Fish liver oil instead of pharmaceuticals? Lakartidningen 1988; Ariza-Ariza R, Mestanza-Peralta M, Cardiel M: Omega-3 fatty acids in rheumatoid arthritis: An overview. Seminars in Arthritis & Rheumatism 1998;27: Axelrod L: Omega-3 fatty acids in diabetes mellitus. Gift from the sea? Diabetes 1989;38: Bagdade JD: HDL and reverse cholesterol transport in diabetes. Diabetes Reviews 1997;5: Barre D: Potential of evening primrose, borage, black currant, and fungal oils in human health. Annals.of.Nutrition.and.Metabolism 2001;45: Barrett PH, Watts GF: HDL kinetics, fish oils and diabetes. Atherosclerosis 2001;159: Barrett PH, Watts GF: Kinetic studies of lipoprotein metabolism in the metabolic syndrome including effects of nutritional interventions. Current Opinion in Lipidology 2003;14: Bates EJ: Eicosanoids, fatty acids and neutrophils: Their relevance to the pathophysiology of disease. Prostaglandins Leukotrienes & Essential Fatty Acids 1995;53: Belaiche J, Louis E: Management of postoperative Crohn's disease recurrence. Acta Endoscopica 1999;29: Belch J: Fish oil and rheumatoid arthritis: Does a herring a day keep rheumatologists away? Annals of the Rheumatic Diseases 1990;49: Belch JJF: Is there a role for natural remedies in rheumatoid arthritis? Scottish Medical Journal 1992;37: Belluzzi A: N-3 and n-6 fatty acids for the treatment of autoimmune diseases. European.Journal.of.Lipid.Science.and.Technology 2001;103: Belluzzi A: N-3 fatty acids for the treatment of inflammatory bowel diseases. Proceedings of the Nutrition Society 2002;61: Belluzzi A, Boschi S, Brignola C, Munarini A, Cariani G, Miglio F: Polyunsaturated fatty acids and inflammatory bowel disease. American Journal of Clinical Nutrition 2000;71:339S-342S. 118

136 Belluzzi A, Boschi S, Miglio F, et al: Long-chain fatty acids for the treatment of inflammatory bowel disease. Essential fatty acids and eicosanoids: invited papers from the Fourth International Congress, Edinburgh, Scotland, UK, July 20 24, ;30: Belluzzi A, Miglio F: n-3 Fatty acids in the treatment of Crohn's Disease. Medicinal Fatty Acids in Inflammation 1998; Berry EM: Dietary fatty acids in the management of diabetes mellitus. American Journal of Clinical Nutrition 1997;66:991S-997S. Berry EM: Who's afraid of n-6 polyunsaturated fatty acids? Methodological considerations for assessing whether they are harmful. Nutrition Metabolism & Cardiovascular Diseases 2001;11: Best JD, O'Neal DN: Diabetic dyslipidaemia: Current treatment recommendations. Drugs 2000;59: Bickston SJ, Cominelli F: Inflammatory Bowel disease: Short- and long- term treatments. Disease-a- Month 1998;44: Bickston SJ, Cominelli F: Recent developments in the medical therapy of inflammatory bowel disease. Current Opinion in Gastroenterology 1998;14:6-10. Bilo HJ, Gans RO: Fish oil: a panacea? Biomedicine & Pharmacotherapy 1990;44: Bilo HJ, Homan van der Heide JJ Gans RO, Donker AJ: Omega-3 polyunsaturated fatty acids in chronic renal insufficiency. Nephron 1991;57: Blok W, Katan M, Van der Meer J: Modulation of inflammation and cytokine production by dietary (n- 3) fatty acids. Journal of Nutrition 1996;126: Boucher BJ: Inadequate vitamin D status: Does it contribute to the disorders compris ing syndrome 'X'? British Journal of Nutrition 1998;79: Buchanan HM, Preston SJ, Brooks PM, Buchanan WW: Is diet important in rheumatoid arthritis? British Journal of Rheumatology 1991;30: Burke A, Lichtenstein GR, Rombeau JL: Nutrition and ulcerative colitis. Baillieres Clinical Gastroenterology 1997;11: Cabre E, Gassull MA: Nutrition in inflammatory bowel disease: Impact on disease and therapy. Current Opinion in Gastroenterology 2001;17: Cabre Gelada I, Esteve Comas I: Polysaturated fatty acids and their metabolites in chronic inflammatory bowel disease. Gastroenterologia y Hepatologia 1995;18: Calder J, Issenman R, Cawdron R: Health information provided by retail health food outlets. Canadian Journal of Gastroenterology 2000;14: Calder PC: Polyunsaturated fatty acids, inflammation, and immunity. Lipids 2001;36: Calder P: Dietary fatty acids and the immune system. Lipids 1999;34:S137-S140 Calder P: Dietary modification of inflammation with lipids. Proceedings of the Nutrition Society 2002;61: Calder P: n-3 polyunsaturated fatty acids and cytokine production in health and disease. Annals of Nutrition & Metabolism 1997;41: Calder P: N-3 polyunsaturated fatty acids, inflammation and immunity: Pouring oil on troubled waters or another fishy tale? Nutrition Research 2001;21: Calder PC, Yaqoob P, Thies F, Wallace FA, Miles EA: Fatty acids and lymphocyte functions. British Journal of Nutrition 2002;87:S31-S48 Calder P, Zurier R: Polyunsaturated fatty acids and rheumatoid arthritis. Current Opinion in Clinical Nutrition & Metabolic Care 2001;4: Callegari PE, Zurier RB: Botanical lipids: potential role in modulation of immunologic responses and inflammatory reactions. Rheumatic Diseases Clinics of North America 1991;17:

137 Campieri M, Gionchetti P, Belluzzi A, Brignola C, Miglioli M, Barbara L: Medical treatment of inflammatory bowel disease. Current Opinion in Gastroenterology 1992;8: Casellas F, Guarner F: Eicosanoids in inflammatory bowel disease. Therapeutic implications. Clinical Immunotherapeutics 1996;6: Cathcart ES, Gonnerman WA, Leslie CA, Hayes KC: Dietary n-3 fatty acids and arthritis. Journal of Internal Medicine Supplement 1989;225: Chowdhury MN: IgA nephropathy and fish oil. Bangladesh Renal Journal 2000;19: Clark W: Treatment of lupus nephritis: Immunosuppression, general therapy, dialysis and transplantation. Clinical & Investigative Medicine 1994;17: Clark WF, Parbtani A: Omega-3 fatty acid supplementation in clinical and experimental lupus nephritis. American Journal of Kidney Diseases 1994;23: Clarke SD: Polyunsaturated fatty acid regulation of gene transcription: a mechanism to improve energy balance and insulin resistance. British Journal of Nutrition 2000;83:S59-S66 Cleland LG, Hill CL, James MJ: Diet and arthritis. Baillieres Clinical Rheumatology 1995;9: Cleland L, James M: Adulthood prevention: Rheumatoid arthritis. Medical Journal of Australia 2002;176:S119-S120 Cleland L, James M: Fish oil and rheumatoid arthritis: Antiinflammatory and collateral health benefits. Journal of Rheumatology 2000;27: Cleland LG, James MJ: Rheumatoid arthritis and the balance of dietary N-6 and N-3 essential fatty acids. British Journal of Rheumatology 1997;36: Cole T, Hawkey CJ: New treatments in inflammatory bowel disease. British Journal of Hospital Medicine 1992;47: Collier GR, Sinclair AJ: Role of N-6 and N-3 fatty acids in the dietary treatment of metabolic disorders. Annals of the New York Academy of Sciences 1993;683: Connor WE: Diabetes, fish oil, and vascular disease. Annals of Internal Medicine 1995;123: Connor WE, DeFrancesco CA, Connor SL: N-3 fatty acids from fish oil. Effects on plasma lipoproteins and hypertriglyceridemic patients. Annals of the New York Academy of Sciences 1993;683: Cortot A, Desreumaux P: Crohn's disease: How to prevent a flare-up. Drugs of Today 1999;35: Cukier C, Waitzberg DL: Biological activity of fish oil. Arquivos.de Gastroenterologia. 1996: D'Amico G: Treatment of IgA nephropathy: An overview. Nephrology 1997;3:S725-S730 D'Haens G, Rutgeerts P: Maintenance and prophylactic therapy for Crohn's disease. Current Opinion in Gastroenterology 1997;13: Darlington LG: Dietary therapy for rheumatoid arthritis. Clinical & Experimental Rheumatology 1994;12: Darlington L: Do diets rich in polyunsaturated fatty acids affect dis ease activity in rheumatoid arthritis? Annals.of.the.Rheumatic.Diseases 1988;47: Darlington LG, Ramsey NW: Review of dietary therapy for rheumatoid arthritis. British Journal of Rheumatology 1993;32: Darlington LG, Ramsey NW: Review of dietary therapy for rheumatoid arthritis. Comprehensive Therapy 1994;20: Darlington L, Stone T: Antioxidants and fatty acids in the amelioration of rheumatoid arthritis and related disorders. British Journal of Nutrition 2001;85: Das U: Beneficial action(s) of eicosapentaenoic acid/docosahexaenoic acid and nitric oxide in systemic lupus erythematosus. Medical Science Research 1995;23:

138 Das UN: Beneficial effect(s) of n-3 fatty acids in cardiovascular diseases: but, why and how? Prostaglandins Leukotrienes & Essential Fatty Acids 2000;63: Das U: Essential fatty acids: Biology and their clinical implications. Asia Pacific Journal of Pharmacology 1991;6: Das UN: Essential fatty acids in health and disease. Journal of the Association of Physicians of India. 1999;47: Das U: Hypothesis: can glucose-insulin-potassium regimen in combination with polyunsaturated fatty acids suppress lupus and other inflammatory conditions? Prostaglandins,.Leukotrienes.and.Essential.Fatty.Aci ds 2001;55: Das U: Interaction(s) between essential fatty acids, eicosanoids, cytokines, growth factors and free radicals: Relevance to new therapeutic strategies in rheumatoid arthritis and other collagen vascular diseases. Prostaglandins Leukotrienes & Essential Fatty Acids 1991;44: Das UN: Interaction(s) between nutrients, essential fatty acids, eicosanoids, free radicals, nitric oxide, anti-oxidants and endothelium and their relationship to human essential hypertension. Medical Science Research 2000;28: Das UN: The lipids that matter from infant nutrition to insulin resistance. Prostaglandins Leukotrienes & Essential Fatty Acids 2002;67:1-12. Das UN: Nutritional factors in the pathobiology of human essential hypertension. Nutrition 2001;139: Daviglus M, Sheeshka J, Murkin E: Health benefits from eating fish. Comments on Toxicology 2002;8: de Caterina R: Omega 3 fatty acids in renal diseases. World Review of Nutrition & Dietetics 1994;76: De Caterina R, Endres S, Kristensen SD, Schmidt EB: n-3 fatty acids and renal diseases. American Journal of Kidney Diseases 1994;24 : De Leeuw IH: Is there a place for N-3 fatty acids in the treatment of diabetic patients? Diabetes, Nutrition & Metabolism - Clinical & Experimental 1991;4: De Strihou CVY: Fish oil for IgA nephropathy? New England Journal of Medicine 1994;331: Dean JD, Durrington PN: Treatment of dyslipoproteinaemia in diabetes mellitus. Diabetic Medicine 1996;13: DeLuca P, Rothman D, Zurier R: Marine and botanical lipids as immunomodulatory and therapeutic agents in the treatment of rheumatoid arthritis. Rheumatic Disease Clinics of North America 1995;21: Dieleman LA, Heizer WD: Nutritional issues in inflammatory bowel disease. Gastroenterology Clinics of North America 1998;27: Diethelm U: Nutrition and chronic polyarthritis. Schweizerische Rundschau.fur Medizin Praxis 1993: Dillon JJ: Fish oil therapy for IgA nephropathy: efficacy and interstudy variability. Journal of the American Society of Nephrology 1997;8: Dillon JJ: Treating IgA nephropathy. Journal of the American Society of Nephrology 2001;12: Donadio JV: n-3 Fatty acids and their role in nephrologic practice. Current Opinion in Nephrology & Hypertension 2001;10: Donadio J: Omega-3 polyunsaturated fatty acids: a potential new treatment of immune renal disease. Mayo Clinic Proceedings. 1991;66: Donadio JV: Use of fish oil to treat patients with immunoglobulin a nephropathy. American Journal of Clinical Nutrition 2000;71:5S Donadio JV, Bergstralh EJ, Grande JP, Rademcher DM: Proteinuria patterns and their association with subsequent end-stage renal disease in IgA nephropathy. Nephrology Dialysis Transplantation 2002;17: Donadio JV, Grande JP: IgA nephropathy. New England Journal of Medicine Online 2002;347:

139 Driss F, Darcet P, Lagarde M, et al: Polyunsaturated fatty acids: drug or food? World Review of Nutrition & Dietetics 1984;43: Empey LR, Fedorak RN: Prostaglandins in inflammatory bowel disease therapy. Canadian Journal of Gastroenterology 1993;7: Endres S, De Caterina R, Schmidt EB, Kristensen SD: n-3 Polyunsaturated fatty acids: Update European Journal of Clinical Investigation 1995;25: Endres S, Eisenhut T, Sinha B: n-3 polyunsaturated fatty acids in the regulation of human cytokine synthesis. Biochemical.Society Transactions. 1995: Endres S, Lorenz R, Loeschke K: Lipid treatment of inflammatory bowel disease. Current Opinion in Clinical Nutrition & Metabolic Care 1999;2: Endres S, von Schacky C: n-3 polyunsaturated fatty acids and human cytokine synthesis. Current Opinion in Lipidology 1996;7: Ergas D, Eilat E, Mendlovic S, Sthoeger Z: n-3 fatty acids and the immune system in autoimmunity. Israel Medical Association Journal: Imaj 2002;4: Ernst E: Complementary and alternative medicine in rheumatology. Best Practice & Research in Clinical Rheumatology 2000;14: Ernst E, Chrubasik S: Phyto-anti-inflammatories: A systemic review of randomized, placebocontrolled, double-blind trials. Rheumatic Disease Clinics of North America 2000;26: Ernst E, Nielsen G, Schmidt E: Fish oils and rheumatoid arthritis. Ugeskrift for Laeger 1994;156: Esteve-Comas M, Gassull MA, Jeppesen PB, Hoy C- E, Mortensen PB: Abnormal fatty acid status in patients with Crohn disease. American Journal of Clinical Nutrition 2001;73: Farmer A, Montori V, Dinneen S, Clar C: Fish oil in people with type 2 diabetes mellitus. Cochrane Database of Systematic Reviews 2001;CD Farrell RJ, Peppercorn MA: Ulcerative colitis. Lancet 2002;359: Feehally J: Immunoglobulin A nephropathy: fish oils and beyond. [Review] [27 refs]. Current Opinion in Nephrology & Hypertension 1996;5: Fernandes G, Venkatraman J: Role of omega-3 fatty acids in health and disease. Nutrition Research 1993;13:S19-S45 Feskens EJ, Kromhout D: Epidemiologic studies on Eskimos and fish intake. Annals of the New York Academy of Sciences 1993;683:9-15. Fisher SE: Nutritional therapy of chronic ulcerative colitis. Journal of Pediatric Gastroenterology & Nutrition 1993;16:224- Fleming CR, Jeejeebhoy KN: Advances in clinical nutrition. Gastroenterology 1994;106: Floege J, Feehally J: IgA nephropathy: Recent developments. Journal of the American Society of Nephrology 2000;11: Floege J, Mertens P: Therapy of patients with IgAnephropathy: a critical appraisal. Kidney & Blood Pressure Research 2000;23: Flynn MAT: Dietary fat and chronic diseases. Bahrain Medical Bulletin 1998;20: Fogazzi GB, Sheerin NS: IgA-associated renal diseases. Current Opinion in Nephrology & Hypertension 1996;5: Forbes A: Crohn's disease -- the role of nutritional therapy. Alimentary Pharmacology and Therapeutics 2002; Fortin P, Lew R, Liang M, et al: Validation of a meta-analysis: The effects of fish oil in rheumatoid arthritis. Journal of Clinical Epidemiology 1995;48: Franz MJ, Bantle JP, Beebe CA, et al: Evidencebased nutrition principles and recommendations for the treatment and prevention of diabetes and related complications. Diabetes Care 2002;25: Friedman AL: Etiology, pathophysiology, diagnosis, and management of chronic renal failure in children. Current Opinion in Pediatrics 1996;8:

140 Friedman M, Brandon DL: Nutritional and health benefits of soy proteins. Journal of Agricultural & Food Chemistry 2001;49: Fung SM, Ferrill MJ, Norton LL: Fish oil therapy in IgA nephropathy. Annals of Pharmacotherapy 1997;31: Garg A: Treatment of diabetic dyslipidemia. American Journal of Cardiology 1998;81:47B-51B. Garg A, Grundy SM: Treating dyslipidemia in patients with non-insulin-dependent diabetes mellitus. Cardiovascular Reviews & Reports 1988;9: Gerster H: The use of n-3 PUFAs (fish oil) in enteral nutrition. International Journal for Vitamin.& Nutrition Research 1995;65:3-20. Geusens P: Lipoids: Omega-3-polyunsaturated fatty acids, their anti-inflammatory role, example of rheumatoid polyarthritis. Nutrition Clinique et Metabolisme 1996;10: Gibson RA: The effect of diets containing fish and fish oils on disease risk factors in humans. Australian & New Zealand Journal of Medicine 1988;18: Gil A: Polyunsaturated fatty acids and inflammatory diseases. Biomedicine & Pharmacotherapy 2002;56: Glassock RJ: The treatment of IgA nephropathy: status at the end of the millenium. Journal of Nephrology 1999;12: Gorson DM, Tobin A, Stenson WF: Fish oil supplementation and ulcerative colitis. Annals of Internal Medicine 1992;117: Graham TO, Kandil HM: Nutritional factors in inflammatory bowel disease. Gastroenterology Clinics of North America 2002;31: Grande JP, Donadio JV: Role of dietary fish oil supplementation in IgA nephropathy. Mechanistic implications. Minerva Urologica e Nefrologica 2001;53: Grassi M, Raffa S, Damiani VC, Fontana M: Current orientation in medical management of ulcerative colitis. Clinica Terapeutica 1995;146: Griffiths AM: Inflammatory bowel disease. Nutrition 1998;14: Grimble RF: Modification of inflammatory aspects of immune function by nutrients. Nutrition Research 1998;18: Grimm H, Mayer K, Mayser P, Eigenbrodt E: Regulatory potential of n-3 fatty acids in immunological and inflammatory processes. British Journal of Nutrition 2002;87:S59-S67 Harris WS: Dietary fish oil and blood lipids. Current Opinion in Lipidology 1996;7:3-7. Hawkey CJ, Mahida YR, Hawthorne AB: Therapeutic interventions in gastrointestinal disease based on an understanding of inflammatory mediators. Agents & Actions 1992;Spec:6 Heine G, Sester U, Kohler H, et al: IgA nephropathy [3] (multiple letters). New England Journal of Medicine 2003;348: Heine RJ: Dietary fish oil and insulin action in humans. Annals of the New York Academy of Sciences 1993;683: Heller A, Koch T, Schmeck J, Van Ackern C: Lipid mediators in inflammatory disorders. Drugs 1998;55: Hitchens K: Managing inflammatory bowel disease. American Druggist 1997;214: Hodgson HJ: Keeping Crohn's disease quiet. New England Journal of Medicine 1996;334: Hogg RJ, Waldo B: Advances in treatment: immunoglobulin A nephropathy. Seminars in Nephrology 1996;16: Horrobin DF: Essential fatty acids and the complications of diabetes mellitus. Wiener Klinische Wochenschrift 1989;101: Horrobin D: Low prevalences of coronary heart disease (CHD), psoriasis, asthma and rheumatoid arthritis in Eskimos: are they casued by high dietary intake of eicosapentaenoic acid (EPA), a genetic variation of essential fatty acid (EFA) metabolism or a combination of. Medical.Hypotheses 1987;26: 123

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155 Shimizu H, Sato N, Tanaka Y, Kashima K, Ohtani K, Mori M: Effect of eicosapentaenoic acid ethyl on urine albumin excretion in NIDDM. Diabetes Care 1993;16: Spannagl M, Drummer C, Froschl H, et al: Plasmatic factors of haemostasis remain essentially unchanged except for PAI activity during n-3 fatty acid intake in type I diabetes mellitus. Blood Coagulation & Fibrinolysis 1991;2: Sperling R, Weinblatt M, Robiin J, Ravalese J, Hoover R, House Fea: Effects of dietary supplementation with marine fish oil on leukoeyte lipid mediators and function in rheumatoid rthritis. Arthritis Rheum 1987;30: Stacpoole PW, Alig J, Ammon L, Crockett SE: Doseresponse effects of dietary marine oil on carbohydrate and lipid metabolism in normal subjects and patients with hypertriglyceridemia. Metabolism: Clinical & Experimental 1989;38: Stacpoole PW, Alig J, Kilgore LL, et al: Lipodystrophic diabetes mellitus. Investigations of lipoprotein metabolism and the effects of omega-3 fatty acid administration in two patients. Metabolism: Clinical & Experimental 1988;37: Stene LC, Ulriksen J, Magnus P, Joner G: Use of cod liver oil during pregnancy associated with lower risk of Type I diabetes in the offspring.[erratum appears in Diabetologia. Diabetologia 2000;43: Stenson W, Cort D, Beeken Wea: A trial of fish oil supplemented diet in ulcerative colitis. Gastroenterology 1990;98:A475 Suci M Katica D, Kovacevi V: Effect of dietary fish supplementation on lipoprotein levels in patients with hyperlipoproteinemia. Collegium Antropologicum 1998;22: Sulikowska B, Manitius J, owski T, ysiak W, Rutkowski B: The effect of therapy with small doses of mega-3 polyunsaturated fatty acid on renal reserve and metabolic disturbances in patients with primary IGA glomerulopathy. Polskie Archiwum Medycyny Wewnetrznej 2002;108: Takahashi R, Inoue J, Ito H, Hibino H: Evening primrose oil and fish oil in non-insulin-dependentdiabetes. Prostaglandins Leukotrienes & Essential Fatty Acids 1993;49: Tilvis RS, Rasi V, Viinikka L, Ylikorkala O, Miettinen TA: Effects of purified fish oil on platelet lipids and function in diabetic women. Clinica Chimica Acta 1987;164 : Tobin A: Eicosapentaenoic acid in chronic ulcerative colitis. Gut 1989;30:A1502 Tsujikawa T, Satoh J, Uda K, et al: Clinical importance of n-3 fatty acid-rich diet and nutritional education for the ma intenance of remission in Crohn's disease. Journal of Gastroenterology 2000;35: van Dam RM, Rimm EB, Willett WC, Stampfer MJ, Hu FB, van Dam RM: Dietary patterns and risk for type 2 diabetes mellitus in U.S. men. Annals of Internal Medicine 2002;136: Vessby B, Karlstrom B, Boberg M, Lithell H, Berne C: Polyunsaturated fatty acids may impair blood glucose control in type 2 diabetic patients. Diabetic Medicine 1992;9: Virstiuk N: English walnuts in the combined treatment of rheumatoid arthritis patients. Likarska.Sprava. 1997;Mar-Apr: Wakai K, Kawamura T, Matsuo S, Hotta N, Ohno Y: Risk factors for IgA nephropathy: a case-control study in Japan. American Journal of Kidney Diseases 1999;33: Wijendran V, Bendel RB, Couch SC, Philipson EH, Cheruku S, Lammi-Keefe CJ: Fetal erythrocyte phospholipid polyunsaturated fatty acids are altered in pregnancy complicated with gestational diabetes mellitus. Lipids 2000;35: Williams CM, Moore F, Wright J: Fasting and postprandial triacylglycerol responses to a standard test meal in subjects taking dietary supplements of n- 3 fatty acids. Biochemical Society Transactions 1990;18:

156 Yosefy C, Viskoper JR, Laszt A, et al: The effect of fish oil on hypertension, plasma lipids and hemostasis in hypertensive, obese, dyslipidemic patients with and without diabetes mellitus. Prostaglandins Leukotrienes & Essential Fatty Acids 1999;61: Zak A, Zeman M, Tvrzicka E, Stolba P: Effects of fish oils in patients with type 2 diabetes with associated dyslipidaemia. Casopis Lekaru Ceskych 1996;135: Zambon S, Friday KE, Childs MT, Fujimoto WY, Bierman EL, Ensinck JW: Effect of glyburide and omega 3 fatty acid dietary supplements on glucose and lipid metabolism in patients with non-insulindependent diabetes mellitus. American Journal of Clinical Nutrition 1992;56:

157 Rejected Duplicate Dunstan DW, Mori TA, Puddey IB, et al: A randomised, controlled study of the effects of aerobic exercise and dietary fish on coagulation and fibrinolytic factors in type 2 diabetics. Thrombosis & Haemostasis 1999;81: Fox J, Manitius J, Debska Slizien A, et al: Influence of omega-3 acids administration on plasma lipids, functional status of erythrocyte membrane and function of the kidney in patients with primary glomerulopathies. Przeglad Lekarski 1996;13:12, Nielsen G, Faarvang K, Tomsen B, Teglbjaerg K, Ernst E: Effects of supplementation with n-3 fatty acids on clinical disease variables in patients with rheumatoid arthritis. European Journal of Clinical Investigation 21: Tulleken J, Limburg P, Muskiet F, van Rijswijk M: Vitamin E status during dietary fish oil supplementation in rheumatoid arthritis. Arthritis Rheum 1990;33:

158 Rejected Unable to Find Translator Faarvang KL, Nielsen GL, Thomsen BS, et al: Fish oils and rheumatoid arthritis. A randomized and double-blind study. Ugeskrift for Laeger 1994;156: Shunto S, Takahashi K, Negishi K, et al: Effects of eicosapentaenoic acid on glycemic control and lipid metabolism in healthy and NIDDM subjects. Therapeutic Research 1992;13: Skoldstam L, Berglund U, Eriksson A, Akesson B: A diet rich in polyunsaturated fatty acids is of no help in patients with rheumatoid arthritis. Lakartidningen 1988;14:4411- Vargova V: Will administration of omega-3 unsaturated fatty acids reduce the use of nonsteroidal antirheumatic agents in children with chronic juvenile arthritis? Casopis.Lekaru.Ceskych. 1998;137:

159 Rejected No difference in Omega-3 Content Buonfantino M, Marano M, Di Nuzzi L, Iorio G, Iuliano P, Tufano L: Use of fatty polyunsaturated acids (Fish oil) in diabetic nephropathy: Results of a preliminary study. Rassegna Internazionale di Clinica e Terapia 1995;75: Dichi I, Frenhane P, Dichi J, et al: Comparison of omega-3 fatty acids and sulfasalazine in ulcerative colitis. Nutrition 2000;16: Gassull MA, Fernandez-Banares F, Cabre E, et al: Fat composition may be a clue to explain the primary therapeutic effect of enteral nutrition in Crohn's disease: results of a double blind randomised multicentre European trial. Gut 2002;51: Haugen MA, Kjeldsen-Kragh J, Bjerve KS, Hostmark AT, Forre O: Changes in plasma phospholipid fatty acids and their relationship to disease activity in rheumatoid arthritis patients treated with a vegetarian diet. British Journal of Nutrition 1994;72: Herrmann W, Biermann J, Ratzmann KP, Lindhofer HG: Effect of fish oil concentrate on the lipoprotein profile of patients with type II diabetes mellitus. Medizinische Klinik 1992;87: Katsuyama H, Ideguchi S, Fukunaga M, Saijoh K, Sunami S: Usual dietary intake of fermented soybeans (Natto) is associated with bone mineral density in premenopausal women. Journal of Nutritional Science & Vitaminology.48(3):207-15, 2002;- Leiper K, Woolner J, Mullan MMC, et al: A randomised controlled trial of high versus low long chain triglyceride whole protein feed in active Crohn's disease. Gut 2001;49: Louheranta AM, Sarkkinen ES, Vidgren HM, Schwab US, Uusitupa MI: Association of the fatty acid profile of serum lipids with glucose and insulin metabolism during 2 fat-modified diets in subjects with impaired glucose tolerance. American Journal of Clinical Nutrition 2002; 76: Potter S, Baum J, Teng H, Stillman RJ, Shay N, Erdman J: Soy protein and isoflavones: their effects on blood lipids and bone density in postmenopausal women. Am J Clin Nutr 1998;68:1375S-1379S. Provenzano C, Vero R, Oliva A, et al: Lispro insulin in type 1 diabetic patients on a Mediterranean or normal diet: a randomized, cross-over comparative study with regular insulin. Diabetes, Nutrition & Metabolism - Clinical & Experimental 2001;14: Rodriguez-Villar C, Manzanares JM, Casals E, et al: High-monounsaturated fat, olive oil-rich diet has effects similar to a high-carbohydrate diet on fasting and postprandial state and metabolic profiles of patients with type 2 diabetes. Metabolism: Clinical & Experimental 2000;49: Sakurai T, Matsui T, Yao T, et al: Short-term efficacy of enteral nutrition in the treatment of active Crohn's disease: a randomized, controlled trial comparing nutrient formulas. Journal of Parenteral & Enteral Nutrition 2002;26: Summers LK, Fielding BA, Bradshaw HA, et al: Substituting dietary saturated fat with polyunsaturated fat changes abdominal fat distribution and improves insulin sensitivity. Diabetologia 2002;45: Leventhal LJ, Boyce EG, Zurier RB: Treatment of rheumatoid arthritis with blackcurrant seed oil. British Journal of Rheumatology 1994;33: Lopez-Espinoza I, Howard -Williams J, Mann JI, Carter RD, Hockaday TD: Fatty acid composition of platelet phospholipids in non-insulin-dependent diabetics randomized for dietary advice. British Journal of Nutrition 1984;52:

160 Rejected No Outcomes or Criteria of Interest Astorga G: Active rheumatoid arthritis: effect of dietary supplementation with omega-3 oils. A controlled double-blind trial. Revista Medica de Chile 1991;119: Belluzzi A, Brignola C, Campieri M, et al: Effects of a new fish oil derivative on fatty acid phospholipidmembrane pattern in a group of Crohn's disease patients. Dig Dis Sci 1994;39: Woodman RJ, Mori TA, Burke V, et al: Effects of purified eicosapentaenoic acid and docosahexaenoic acid on platelet, fibrinolytic and vascular function in hypertensive type 2 diabetic patients. Atherosclerosis 2003;166: Dahlan W, Richelle M, Kulapongse S, Rossle C, Deckelbaum RJ, Carpentier YA: Effects of essential fatty acid contents of lipid emulsions on erythrocyte polyunsaturated fatty acid composition in patients on long-term parenteral nutrition. Clinical Nutrition 1992;11: Espersen G, Grunnet N, Lervang H, et al: Decreased interleukin-1 beta levels in plasma from rheumatoid arthritis patients after dietary supplementation with n- 3 polyunsaturated fatty acids. Clinical Rheumatology 1992;11: Hillier K: Human colon mucosa: effect of marine oils on lipid fatty acid composition and eicosanoid synthesis in inflammatory bowel disease. British Journal of Clinical Pharmacology 1988;25:129P- 30P. Hillier K, Jewell R, Dorrell L, Smith C: Incorporation of fatty acids from fish oil and olive oil into colonic mucosal lipids and effects upon eicosanoid synthesis in inflammatory bowel disease. Gut 1991;32: Ikehata A, Hiwatashi N, Kinouchi Y, et al: Effect of intravenously infused eicosapentaenoic acid on the leukotriene generation in patients with active Crohn's disease. American Journal of Clinical Nutrition 1992;56: Jantti JV, Vapaatalo H, Seppala E, Ruutsalo HM, Isomaki H: Treatment of rheumatoid arthritis with fish oil, selenium, vitamins A and E, and placebo. Scandinavian Journal of Rheumatology 1991;20:225 Rubin M, Moser A, Vaserberg N, et al: Structured triacylglycerol emulsion, containing both mediumand long-chain fatty acids, in long-term home parenteral nutrition: a double-blind randomized cross-over study. Nutrition 2000;23:2,

161 Almallah Y, Ewen S, El Tahir A, et al: Distal proctocolitis and n-3 polyunsaturated fatty acids (n-3 PUFAs): the mucosal effect in situ. Journal of Clinical Immunology 2000;20: Chan D, Watts G, Barrett P, Beilin L, Redgrave T, Mori T: Regulatory effects of HMG CoA reductase inhibitor and fish oils on apolipoprotein B-100 kinetics in insulin-resistant obese male subjects with dyslipidemia. Diabetes 2002;51: Dunstan D, Mori T, Puddey I, et al: The independent and combined effects of aerobic exercise and dietary fish intake on serum lipids and glycemic control in NIDDM. A randomized controlled study. Diabetes Care 1997;20: McVeigh G, Brennan G, Cohn J, Finkelstein S, Hayes R, Johnston G: Fish oil improves arterial compliance in non-insulin-dependent diabetes mellitus. Arteriosclerosis & Thrombosis 1994;14: McVeigh G, Brennan G, Johnston G, et al: Dietary fish oil augments nitric oxide production or release in patients with type 2 (non-insulin-dependent) diabetes mellitus. Diabetologia 1993;36: Mori T, Dunstan D, Burke V, et al: Effect of dietary fish and exercise training on urinary F2-isoprostane excretion in non-insulin-dependent diabetic patients. Metabolism: Clinical & Experimental 1999;48: Nielsen G, Faarvang K, Tomsen B, Teglbjaerg K, Ernst E: Effects of supplementation with n-3 fatty acids on clinical disease variables in patients with rheumatoid arthritis. European Journal of Clinical Investigation 21: Duplicate Reports of Same Trial 144

162 145

163 Appendix A. Methodologic Approach A.1 Preliminary Research Questions A.2 Technical Expert Panel A.3 Search Strategies A.4 Inclusion/Exclusion Criteria A.5 Evidence Grading System A.6 External Peer Reviewer

164 A.1 Preliminary Research Questions Table A.1.1. Preliminary research questions. GENERAL QUESTIONS : Questions posed for all three participating EPCs, for years 1 and What is the evidence that variable clinical effects may reflect differences in: Serving size (fish vs. dietary supplement); Source (fis h, food, plant) vs. dietary supplement (fish oil, plant oil); Specific type(s) of omega-3 fatty acids (docosahexaenoic acid (DHA), eicosapentaenoic acid (EPA), docosapentaenoic acid (DPA), and alpha-linolenic acid (ALA), fish, fish oil), or the ratio of om ega- 6/omega-3 fatty acids used; Manufacturer (different purity, presence of other potentially active agents)? 2. What is the evidence for adverse events, side effects, or counter-indications associated with omega-3 fatty acids (DHA, EPA, DPA, ALA, fish oil, fish)? 3. What is the evidence that omega-3 fatty acids are associated with adverse events in specific subpopulations such as diabetics? 4. What are the mean and median intakes of DHA, EPA, DPA, ALA, fish, fish oil, omega-6, omega-6/omega-3 ratio in the US population? 5. What is the evidence that omega-3 fatty acids influence overall energy balance? 6. What is the evidence that accurate interpretation of the results of clinical studies is dependent on knowing the absolute fatty acid content of the baseline data, the relative fatty acid content of the baseline diet, or the tissue ratios of fatty acids (omega-6/omega-3) during the investigative period? DISEASE-SPECIFIC QUESTIONS : questions posed to the SCEPC for Year 1 of the project: Immune-Mediated Diseases 1. What is the evidence that in adults or children with type I diabetes, omega-3 fatty acids increase insulin sensitivity? 2. What is the evidence that in adults or children with rheumatoid arthritis, omega-3 fatty acids decrease pain or the number of swollen joints? 3. What is the evidence that omega-3 fatty acids help maintain bone mineral status? 4. What is the evidence that in adults or children with inflammatory bowel disease (ulcerative colitis and Chrohn s disease), omega-3 fatty acids lower leukotriene B4 or prostaglandin E2 levels? 5. What is the evidence that in adults or children with systemic lupus erythematosis, omega-3 fatty acids prolong longevity? Gastrointestinal/Renal 1. What is the evidence for the efficacy of omega-3 fatty acids in treatment of Crohn s disease, ulcerative colitis, renal inflammation, and glomerulosclerosis? 2. What is the evidence for the efficacy of omega-3 fatty acids in treatment of the hypertriglyceridemia of type II diabetes, insulin resistance, or the metabolic syndrome? 3. What is the evidence that omega-3 fatty acids influence the regulation of gene expression in the progression/prevention of obesity, and intestinal and liver diseases? 152

165 A.2 Technical Expert Panel The members of our technical expert panels are listed in Table A.2.1. We conducted our TEP meetings via teleconference. We held a conference call with the rheumatoid arthritis, systemic lupus erythematosis, and bone density TEP on February 7, 2003; the renal/diabetes TEP on February 12, 2003; and the gastrointestinal TEP on February 12, Dr. Rosaly Correa-de- Araujo, the Task Order Officer, and Jacqueline Besteman, Director of the Evidence-Based Practice Center Program, represented AHRQ on these calls; Dr. Anne Thurn, Director of the Evidence-Based Review Program, represented ODS; and Dr. Paul Shekelle, Director of the SCEPC, Dr. Catherine MacLean, the Task Order Director, and Rena Hasenfeld, the Project Manager, represented the SCEPC. The key comments and recommendations of each TEP are summarized in Table A.2.2. The TEP continued to advise the SCEPC throughout the project via mail, fax, , and phone calls. Table A.2.1 Technical expert panel members. Rheumatoid Arthritis, Systemic Lupus Erythematosis, and Bone Density TEP Name Area of Expertise Institution Judith Ashley, PhD, MSPH, RD Omega-3 Fatty Acids University of Nevada School of Medicine William S. Harris, PhD Omega-3 Fatty Acids University of Missouri-Kansas City School of Medicine Robert P. Heaney, MD Bone Creighton University David A. Isenberg, MD SLE University College London Medical School Joel Kremer, MD Rheumatoid Arthritis The Center for Rheumatology Bruce A. Watkins, PhD Omega-3 Fatty Acids Purdue University Josiah F. Wedgwood, MD, PhD Rheumatoid Arthritis National Institute of Allergy and Infectious Diseases Renal Disease and Diabetes TEP Name Area of Expertise Institution Judith Ashley, PhD, MSPH, RD Omega-3 Fatty Acids University of Nevada School of Medicine Mayer B. Davidson, MD Diabetes Charles R. Drew University of Medicine and Science James V. Donadio, MD Renal Diseases Mayo Medical School William S. Harris, PhD Omega-3 Fatty Acids University of Missouri-Kansas City School of Medicine Michael D. Jensen, MD Diabetes Mayo Medical School William F. Keane, MD Renal Diseases Merck and Co., Inc. Catherine Meyers, MD Renal Diseases NIDDK, Division of Kidney, Urologic & Hematologic Diseases Gastrointestinal Diseases TEP Name Area of Expertise Institution Judith Ashley, PhD, MSPH, RD Omega-3 Fatty Acids University of Nevada School of Medicine Andrea Belluzzi, MD Irritable Bowel Disease S Orsola Hospital, Bologna, Italy Frank Hamilton, MD Irritable Bowel Disease NIDDK, Division of Digestive Diseases & Nutrition William S. Harris, PhD Omega-3 Fatty Acids University of Missouri-Kansas City School of Medicine Stephen James, MD Inflammatory Bowel Disease NIDDK, Division of Digestive Diseases & Nutrition Michael Ken May, PhD Inflammatory Bowel Disease NIDDK, Division of Digestive Diseases & Nutrition William F. Stenson, MD Inflammatory Bowel Disease Washington University Table A.2.2. Key TEP comments and recommendations. Rheumatoid Arthritis, Systemic Lupus Erythematosis, and Bone Density TEP 1. What is the evidence that in adults or children with rheumatoid arthritis, omega-3 fatty acids decrease pain or the number of swollen joints? Restrict the search to randomized control trials. Include children with juvenile rheumatoid arthritis for now. If possible, the outcome measures should include: disease activity, damage, and patient perception (i.e. patient global assessment). 153

166 2. What is the evidence that omega-3 fatty acids help maintain bone mineral status? Include both randomized controlled trials and observational studies. The populations of interest are older women and women with osteoporosis. Outcomes for randomized controlled trials will likely be measures of bone density and biologic markers. Outcomes for observational studies are more likely to include fracture rates. There is a need to adjust for ethnicity in the analyses because bone shape may affect the rate of fractures. In studies that report t-scores, there is a need to note the standard used to compute the t-score; WHO and NHANES are two different standards that may be used. 3. What is the evidence that in adults or children with systemic lupus erythematosus, omega-3 fatty acids prolong longevity? Restrict the study to randomized controlled trials. Longevity is not the correct outcome to assess. Recommended outcomes for assessment include disease activity, damage, and patient perception (i.e. patient global assessment). General Comments Note reported side effects of omega-3 fatty acids when reviewing the literature. Renal Disease and Diabetes TEP 1. What is the evidence for the efficacy of omega-3 fatty acids in treatment of hypertriglyceridemia of type II diabetes, insulin resistance, or the metabolic syndrome? The question should be re-worded in the following way: What is the evidence in adults or children for the efficacy of omega-3 fatty acids in treatment of hyperlipedemia in a) type II diabetes, or b) insulin resistance/the metabolic syndrome? Do not to limit the review to hypertriglyceridemia; collect data on other lipids, as well. The question pertains specifically to the effect of omega-3 fatty acids on lipids in two different clinical syndromes: type II DM and the insulin resistance/metabolic syndrome. The question pertains to both adults and children. 2. What is the evidence that in adults or children with type I diabetes, omega-3 fatty acids increase insulin sensitivity? Since insulin resistance is not a feature of type I diabetes, the questions should be re-worded in the following way: What is the evidence in adults and children for an effect of omega-3 fatty acids on insulin sensitivity in a) type II diabetes, or b) the metabolic syndrome? 3. What is the evidence for the efficacy of omega-3 fatty acids in treatment of renal inflammation and glomerulosclerosis? There was no consensus on how renal inflammation and glomerulosclerosis should be defined. There was no consensus about whether to assess the effect of omega-3 fatty acids on the progression of renal disease. Randomized controlled trials should be examined to determine whether sufficient evidence exists to assess the effect of omega-3 fatty acids on renal inflammation and/or the progression of renal acute or chronic renal insufficiency. The question may be re-worded after the literature review has been completed. 154

167 Table A.2.2. Key TEP comments and recommendations (continued). Gastrointestinal Diseases TEP 1. What is the evidence for the efficacy of omega-3 fatty acids in treatment of Crohn s disease and ulcerative colitis? There are so few studies on the efficacy of omega-3 fatty acids in treating inflammatory bowel disease that it may be necessary to do a qualitative rather than a quantitative review of the literature. Efficacy is not uniformly defined in IBD. However, a recent NIH conference addressed defining efficacy in Crohn s disease. There are many potential confounders/effect modifiers for IBD, especially for Crohn s disease, including disease characteristics (severity, presence or absence of fistulas in Crohn s), medication use, and population characteristics. 2. What is the evidence that in adults or children with inflammatory bowel disease (ulcerative colitis and Crohn s disease), omega-3 fatty acids lower leukotriene B4 or prostaglandin E2 levels? A review of the effect of omega-3 fatty acids on leukotriene B4 or prostaglandin E2 should not be included in the report since neither is a measure of prevention or efficacy in IBD. There are no studies of the effects of omega-3 fatty acids on IBD in children. General Comments Take note of the omega-3 preparation. Abstract and report side effects. 155

168 A.3 Search Strategies Table A.3.1. Core search strategy. 1. exp fatty acids, omega-3/ 2. fatty acids, essential/ 3. Dietary Fats, Unsaturated/ 4. linolenic acids/ 5. exp fish oils/ 6. (n 3 fatty acid$ or omega 3).tw. 7. docosahexa?noic.tw,hw,rw. 8. eicosapenta?noic.tw,hw,rw. 9. alpha linolenic.tw,hw,rw. 10. (linolenate or cervonic or timnodonic).tw,hw,rw. 11. menhaden oil$.tw,hw,rw. 12. (mediterranean adj diet$).tw. 13. ((flax or flaxseed or flax seed or linseed or rape seed or rapeseed or canola or soy or soybean or walnut or mustard seed) adj2 oil$).tw. 14. (walnut$ or butternut$ or soybean$ or pumpkin seed$).tw. 15. (fish adj2 oil$).tw. 16. (cod liver oil$ or marine oil$ or marine fat$).tw. 17. (salmon or mackerel or herring or tuna or halibut or seal or seaweed or anchov$).tw. 18. (fish consumption or fish intake or (fish adj2 diet$)).tw. 19. diet$ fatty acid$.tw. 20. or/ dietary fats/ 22. (randomized controlled trial or clinical trial or controlled clinical trial or evaluation studies or multicenter study).pt. 23. random$.tw. 24. exp clinical trials/ or evaluation studies/ 25. follow-up studies/ or prospective studies/ 26. or/ and (Ropufa or MaxEPA or Omacor or Efamed or ResQ or Epagis or Almarin or Coromega).tw. 29. (omega 3 or n 3).mp. 30. (polyunsaturated fat$ or pufa or dha or epa or long chain or longchain or lc$).mp and or 27 or 28 or

169 Table A.3.2. Literature searches by disease category. Diabetes 1. exp fatty acids, omega-3/ 2. fatty acids, essential/ 3. Dietary Fats, Unsaturated/ 4. linolenic acids/ 5. exp fish oils/ 6. (n 3 fatty acid$ or omega 3).tw. 7. docosahexa?noic.tw,hw,rw. 8. eicosapenta?noic.tw,hw,rw. 9. alpha linolenic.tw,hw,rw. 10. (linolenate or cervonic or timnodonic).tw,hw,rw. 11. menhaden oil$.tw,hw,rw. 12. (mediterranean adj diet$).tw. 13. ((flax or flaxseed or flax seed or linseed or rape seed or rapeseed or canola or soy or soybean or walnut or mustard seed) adj2 oil$).tw. 14. (walnut$ or butternut$ or soybean$ or pumpkin seed$).tw. 15. (fish adj2 oil$).tw. 16. (cod liver oil$ or marine oil$ or marine fat$).tw. 17. (salmon or mackerel or herring or tuna or halibut or seal or seaweed or anchov$).tw. 18. (fish consumption or fish intake or (fish adj2 diet$)).tw. 19. diet$ fatty acid$.tw. 20. or/ dietary fats/ 22. (randomized controlled trial or clinical trial or controlled clinical trial or evaluation studies or multicenter study).pt. 23. random$.tw. 24. exp clinical trials/ or evaluation studies/ 25. follow-up studies/ or prospective studies/ 26. or/ and (Ropufa or MaxEPA or Omacor or Efamed or ResQ or Epagis or Almarin or Coromega).tw. 29. (omega 3 or n 3).mp. 30. (polyunsaturated fat$ or pufa or dha or epa or long chain or longchain or lc$).mp and or 27 or 28 or hyperinsulin?emia.tw. 34. hyperinsulinemia/ 35. exp diabetes mellitus/ 36. diabetes.tw. 37. insulin.tw. 38. metabolic syndrome$.tw. 39. exp insulin resistance/ 40. or/ and and human/ 157

170 Table A.3.2. Literature searches by disease category (continued). Inflammatory Bowel Disease and Renal Disease 1. exp fatty acids, omega-3/ 2. fatty acids, essential/ 3. Dietary Fats, Unsaturated/ 4. linolenic acids/ 5. exp fish oils/ 6. (n 3 fatty acid$ or omega 3).tw. 7. docosahexa?noic.tw,hw,rw. 8. eicosapenta?noic.tw,hw,rw. 9. alpha linolenic.tw,hw,rw. 10. (linolenate or cervonic or timnodonic).tw,hw,rw. 11. menhaden oil$.tw,hw,rw. 12. (mediterranean adj diet$).tw. 13. ((flax or flaxseed or flax seed or linseed or rape seed or rapeseed or canola or soy or soybean or walnut or mustard seed) adj2 oil$).tw. 14. (walnut$ or butternut$ or soybean$ or pumpkin seed$).tw. 15. (fish adj2 oil$).tw. 16. (cod liver oil$ or marine oil$ or marine fat$).tw. 17. (salmon or mackerel or herring or tuna or halibut or seal or seaweed or anchov$).tw. 18. (fish consumption or fish intake or (fish adj2 diet$)).tw. 19. diet$ fatty acid$.tw. 20. or/ dietary fats/ 22. (randomized controlled trial or clinical trial or controlled clinical trial or evaluation studies or multicenter study).pt. 23. random$.tw. 24. exp clinical trials/ or evaluation studies/ 25. follow-up studies/ or prospective studies/ 26. or/ and (Ropufa or MaxEPA or Omacor or Efamed or ResQ or Epagis or Almarin or Coromega).tw. 29. (omega 3 or n 3).mp. 30. (polyunsaturated fat$ or pufa or dha or epa or long chain or longchain or lc$).mp and or 27 or 28 or exp inflammatory bowel diseases/ 34. inflammatory bowel.tw. 35. (hemorrhagic proctocolitis or ulcerative proctocolitis).tw. 36. (hemorrhagic rectocolitis or ulcerative rectocolitis).tw. 37. (ileocolitis or ileitis or enteritis or crohn$ or pancolitis or proctitis or colitis).tw. 38. exp nephritis/ 39. ((renal or kidney) and inflammation).tw. 40. (glomerulo$ or nephritis or nephropath$).tw. 41. or/ and and human/ 158

171 Table A.3.2. Literature searches by disease category (continued). Rheumatoid Arthritis 1. exp fatty acids, omega-3/ 2. fatty acids, essential/ 3. Dietary Fats, Unsaturated/ 4. linolenic acids/ 5. exp fish oils/ 6. (n 3 fatty acid$ or omega 3).tw. 7. docosahexa?noic.tw,hw,rw. 8. eicosapenta?noic.tw,hw,rw. 9. alpha linolenic.tw,hw,rw. 10. (linolenate or cervonic or timnodonic).tw,hw,rw. 11. menhaden oil$.tw,hw,rw. 12. (mediterranean adj diet$).tw. 13. ((flax or flaxseed or flax seed or linseed or rape seed or rapeseed or canola or soy or soybean or walnut or mustard seed) adj2 oil$).tw. 14. (walnut$ or butternut$ or soybean$ or pumpkin seed$).tw. 15. (fish adj2 oil$).tw. 16. (cod liver oil$ or marine oil$ or marine fat$).tw. 17. (salmon or mackerel or herring or tuna or halibut or seal or seaweed or anchov$).tw. 18. (fish consumption or fish intake or (fish adj2 diet$)).tw. 19. diet$ fatty acid$.tw. 20. or/ dietary fats/ 22. (randomized controlled trial or clinical trial or controlled clinical trial or evaluation studies or multicenter study).pt. 23. random$.tw. 24. exp clinical trials/ or evaluation studies/ 25. follow-up studies/ or prospective studies/ 26. or/ and (Ropufa or MaxEPA or Omacor or Efamed or ResQ or Epagis or Almarin or Coromega).tw. 29. (omega 3 or n 3).mp. 30. (polyunsaturated fat$ or pufa or dha or epa or long chain or longchain or lc$).mp and or 27 or 28 or exp arthritis, rheumatoid/ 34. (rheumat$ adj2 arthritis).tw. 35. stills diseas$.tw. 36. caplans syndrome$.tw. 37. feltys syndrome$.tw. 38. rheumatoid nodule$.tw. 39. sjogrens syndrome$.tw. 40. ankylosing spondylitis.tw. 41. rheumat$.tw. 42. or/ and limit 43 to human 159

172 Table A.3.2. Literature searches by disease category (continued). Systemic Lupus Erythematosus 1. exp fatty acids, omega-3/ 2. fatty acids, essential/ 3. Dietary Fats, Unsaturated/ 4. linolenic acids/ 5. exp fish oils/ 6. (n 3 fatty acid$ or omega 3).tw. 7. docosahexa?noic.tw,hw,rw. 8. eicosapenta?noic.tw,hw,rw. 9. alpha linolenic.tw,hw,rw. 10. (linolenate or cervonic or timnodonic).tw,hw,rw. 11. menhaden oil$.tw,hw,rw. 12. (mediterranean adj diet$).tw. 13. ((flax or flaxseed or flax seed or linseed or rape seed or rapeseed or canola or soy or soybean or walnut or mustard seed) adj2 oil$).tw. 14. (walnut$ or butternut$ or soybean$ or pumpkin seed$).tw. 15. (fish adj2 oil$).tw. 16. (cod liver oil$ or marine oil$ or marine fat$).tw. 17. (salmon or mackerel or herring or tuna or halibut or seal or seaweed or anchov$).tw. 18. (fish consumption or fish intake or (fish adj2 diet$)).tw. 19. diet$ fatty acid$.tw. 20. or/ dietary fats/ 22. (randomized controlled trial or clinical trial or controlled clinical trial or evaluation studies or multicenter study).pt. 23. random$.tw. 24. exp clinical trials/ or evaluation studies/ 25. follow-up studies/ or prospective studies/ 26. or/ and (Ropufa or MaxEPA or Omacor or Efamed or ResQ or Epagis or Almarin or Coromega).tw. 29. (omega 3 or n 3).mp. 30. (polyunsaturated fat$ or pufa or dha or epa or long chain or longchain or lc$).mp and or 27 or 28 or exp Lupus Erythematosus, Systemic/ 34. (lupus glomerulonephritis or lupus nephritis).tw. 35. (libman-sacks or lupus erythematosus disseminatus or systemic lupus erythematosus).tw. 36. (lupus vasculitis or lupus meningoencephalitis or central nervous system systemic lupus).tw. 37. or/ and limit 38 to human 160

173 Table A.3.2. Literature searches by disease category (continued). Bone Density/Osteoporosis 1. exp fatty acids, omega-3/ 2. fatty acids, essential/ 3. Dietary Fats, Unsaturated/ 4. linolenic acids/ 5. exp fish oils/ 6. (n 3 fatty acid$ or omega 3).tw. 7. docosahexa?noic.tw,hw,rw. 8. eicosapenta?noic.tw,hw,rw. 9. alpha linolenic.tw,hw,rw. 10. (linolenate or cervonic or timnodonic).tw,hw,rw. 11. menhaden oil$.tw,hw,rw. 12. (mediterranean adj diet$).tw. 13. ((flax or flaxseed or flax seed or linseed or rape seed or rapeseed or canola or soy or soybean or walnut or mustard seed) adj2 oil$).tw. 14. (walnut$ or butternut$ or soybean$ or pumpkin seed$).tw. 15. (fish adj2 oil$).tw. 16. (cod liver oil$ or marine oil$ or marine fat$).tw. 17. (salmon or mackerel or herring or tuna or halibut or seal or seaweed or anchov$).tw. 18. (fish consumption or fish intake or (fish adj2 diet$)).tw. 19. diet$ fatty acid$.tw. 20. or/ dietary fats/ 22. (randomized controlled trial or clinical trial or controlled clinical trial or evaluation studies or multicenter study).pt. 23. random$.tw. 24. exp clinical trials/ or evaluation studies/ 25. follow-up studies/ or prospective studies/ 26. or/ and (Ropufa or MaxEPA or Omacor or Efamed or ResQ or Epagis or Almarin or Coromega).tw. 29. (omega 3 or n 3).mp. 30. (polyunsaturated fat$ or pufa or dha or epa or long chain or longchain or lc$).mp and or 27 or 28 or bone density/ 34. (bone mineral or bone densit$ or bone mass).tw. 35. exp Bone Demineralization, Pathologic/ 36. Bone Demineral$.tw. 37. exp Bone Resorption/ 38. (bone loss$ or bone resportion).tw. 39. exp Densitometry/ 40. or/ and limit 41 to human 161

174 Table A.3.3. Industry experts that were contacted for data about efficacy of omega-3 fatty acids. Name Ian Newton Herb Wool, PhD Annette Dickinson Affiliation Roche Vitamins BASF Corporation Council for Responsible Nutrition Figure A.3.1. Letter sent to industry experts. Date Name Address City, State, Zip Code Dear XXX, I am writing on behalf of the Evidence Based Practice Centers at RAND, New England Medical Center and the University of Ottawa. We are conducting a systematic review of the efficacy and toxicity of omega-3 fatty acids in the prevention and treatment of a number of different diseases/conditions. This review is being conducted under a contract from the Agency for Healthcare Research and Quality (AHRQ). We are contacting you to see if there is any evidence, including unpublished evidence, that you want considered. Our focus is on clinical trials of omega-3 fatty acids in humans, so animal and chemical studies are not necessary. The specific questions that all the EPCs will address are detailed in the attachment to this letter. Please contact me with any information that you might have. Best regards, Catherine MacLean, M.D., Ph.D. RAND1700 Main Street, M 23-C Santa Monica, CA Voice: , x6364 Fax:

175 A.4 Inclusion/Exclusion Criteria Table A.4.1. Inclusion/Exclusion Criteria at Screening Stage.* Assessed the effect of omega-3 fatty acids on arthritis (including rheumatoid arthritis and juvenile rheumatoid arthritis), bone mineral metabolism, diabetes, IBD, lupus, or renal disease Presented research on human subjects Reported the results of randomized or controlled clinical trials or cohort/case control studies; we accepted observational studies for bone mineral status only. For cross-over studies, reported outcomes for each arm before the cross-over at the end of the first phase of treatment *Language was not a barrier to inclusion; We defined a randomized controlled trial (RCT) as one in which the participants were assigned to one of two (or more) study groups using a process of random allocation (e.g., random number generation, coin flips); we defined a controlled clinical trial (CCT) as one in which participants were either: (1) assigned to one of two (or more) study groups using a quasirandom allocation method (e.g., alternation, date of birth, patient identifier), or (2) possibly assigned to one of two (or more) study groups using a process of random or quasi-random allocation; We did not use data from the end of the study period in studies with a cross-over design because as a result of this design, the treatment and placebo groups from these studies are not comparable to the treatment and placebo groups of the non-cross-over randomized controlled trials with which they would be pooled in a meta-analysis. For example, one half of the placebo group in a cross-over trial will have been exposed to treatment with omega-3 fatty acids prior to placebo and hence the measured effect could be biased by earlier treatment with Omega-3 fatty acids. 163

176 A.5 Evidence Grading System Table A.5.1. Summary Score for Methodologic Quality. Summary Score Jadad Score Concealment of Allocation A 5 Performed 5 Not performed, or Not reported B 3 or 4 Performed, Not performed, or Not reported 0,1, or 2 Performed C 0, 1, or 2 Not performed or not reported Even though a study may focus on a specific target population, limited study size, eligibility criteria and patient recruitment process may result in a narrow population sample that is of limited applicability, even to the target population. To capture this parameter, we categorize studies into the applicability scale described in Table A.5.1. Table A.5.2 Applicability ratings. Applicability Health state I II III Sample is representative of the U.S. population. Sample is representative of a relevant sub-group of the target population, but not the entire population. For example, a study that is restricted to women or a fish oil study in Japan where the background diet is very different from that of the US would fall into this category. Sample is representative of a narrow subgroup of subjects only, and not well applicable to other subgroups. For example, a study of oldest old men or a study of a population on highly controlled diet. A General population. Typical healthy people similar to Americans without known cardiovascular diseases. B Diseased population. Subjects with any of the following: inflammatory bowel disease, rheumatoid arthritis, renal disease, systemic lupus erythematosus or osteoporosis. 164

177 Figure A.5.1 Jadad score of methodologic quality.* Was the study described as randomized? Was there a description of withdrawals and dropouts? Was the study double-blind? Yes = add 1 point No = 0 points Yes = add 1 point No = 0 points Yes = add 1 point No = 0 points If method of randomization described, was it appropriate? If method of blinding described, was it appropriate? Yes = add 1 point No = 0 points Yes = add 1 point No = 0 points * Jadad A, Moore A, Carrol D, et al. Assessing the quality of reports of randomized clinical trials: Is blinding necessary? Control Clin Trials. 1996;17:

178 Table A.6.1. Peer Reviewers. Peer Reviewer Area of Expertise Affiliation Charles Bernstein, MD Inflammatory Bowel Disease University of Manitoba Richard Glassock, MD nephrology UCLA David Heber, MD nutrition UCLA Ted Kraegen, PhD diabetes, nutrition Garvan Research Institute, Sydney Kenneth Saag, MD, MPH osteoporosis, SLE University of Alabama Walter Willett, MD epidemiology, nutrition Harvard University Robert Zurier, MD rheumatoid arthritis, omega-3 fatty acids University of Massachusetts Medical School 166

179 Appendix B. Coding/Data Abstraction Forms B.2 Literature Screener Form B.3 Quality review form 167

180 1. Article ID: 2. First Author: (Last name of first author) 3. Reviewer: Omega 3 Screening Form Final Version 4. Research intervention topic: (circle one) Omega 3 or synonymous topic... 1 Unclear, no English abstract... 8 (If unclear, skip to question 8 on language) None of the above... 9 (STOP) 5. Condition(s)/Subject(s) studied: (check all that apply) Arthritis (RA, JRA)... Bone mineral metabolism... Diabetes... IBD... Lupus... Renal... (If any of the above conditions are checked, ignore stop codes for the following conditions listed below) Other conditions: Asthma... (STOP) Cancer... (STOP) CVD... (STOP) Child/maternal health... (STOP) Cognitive function... (STOP) Eye health... (STOP) Mental health... (STOP) Neurological disease... (STOP) Organ transplant... (STOP) None of the above... (STOP) 7. Study design:... (circle one) Descriptive (historical, editorial, etc.)... 1 (STOP) Review/ meta-analysis... 2 (STOP) Randomized clinical trial... 3 Controlled clinical trial... 4 Cohort /Case control... 5 (For cohort/case control, if condition not Bone, then STOP) Case Series/Case Report... 6 (STOP) Other (specify: )... 8 (STOP) 8. Language of article: (circle one) English... 1 German... 2 French... 3 Italian... 4 Danish... 5 Other (specify: ) Do you think this article might be a duplicate or include the same data as another study? Yes... 1 No... 2 Notes: 6. Study population: (check all that apply) Human... Animal... (STOP) Unclear... (STOP) Other (specify: )... (STOP) 168

181 Article ID: Reviewer: First Author: (Last Name Only) Study Number: of Description: (Enter 1of 1 if only one) (if more than one study) RAND EPC, Omega-3 Project Quality Review Form 1. Is there a difference in Omega-3 content between arms: (CIRCLE ONE) Yes 1 No 2 (STOP) Unclear 8 (STOP) 2. Design: (CIRCLE ONE) RCT 1 CCT 2 Cohort or Case Control (Bone only) 3 Other design... 4 (STOP) (STOP IF C OHORT/CASE CONTROL AND NOT B ONE OR IF OTHER DESIGN) 3. Does the disease meet the appropriate criteria? Is/are the outcome(s) of interest reported? (CHECK ALL THAT APPLY) NOTE: for conditions to continue, both criteria and outcomes must be met. CRITERIA OUTCOME(S) RA SLE Bone Mineral Density Type I Diabetes Type II Diabetes Metabolic Syndrome NOTE: for each condition to continue only one criteria must be met. Crohn s Disease... Ulcerative colitis... Renal inflammation... Glomerulosclerosis... IgA Nephropathy... Chronic renal disease... Study does not report required components... (STOP) (SEE THE CODE S HEET FOR APPROPRIATE CRITERIA AND OUTCOMES OF INTEREST.) 4. Is the study described as randomized?(circle ONE) Yes 1 No If the study was randomized, was method of randomization appropriate? Yes 1 No 2 Method not described 8 Not applicable (not randomized)...9 (CIRCLE ONE) 6. Is the study described as: (CIRCLE ONE) Double blind 1 Single blind, patient...2 Single blind, outcome assessment...3 Open 4 Blinding not described 8 Not applicable If reported, was the method of double blinding appropriate? Yes 1 No 2 Double blinding method not described...8 Not applicable...9 (CIRCLE ONE) 8. If study was randomized, did the method of randomization provide for concealment of allocation? Yes 1 No...2 Concealment not described...8 Not applicable (not randomized)...9 (CIRCLE ONE) 169

182 9. Are withdrawals (W) and dropouts (D) described? (CIRCLE ONE) Yes, reason described for all W and D 1 Yes, reason described for some W and D... 2 Not described... 8 Not applicable Is this a cross-over study design? (CIRCLE ONE) Yes 1 No... 2 Not described Does the study population represent (CHECK ALL THAT APPLY) HealthyDiseased Typical people... Atypical people... (in terms of diet, SES, other factors) Narrow, atypical people... (including highly controlled diet) Cannot categorize... (incomplete data) 12. What was the number of sites involved in the study? (ENTER NUMBER OF 99 IF NOT REPORTED) 13. In what country was the study conducted? (CHECK ALL THAT APPLY) US UK Japan China Italy Netherlands Canada Other (enter code)...,,, Not specified Are data reported separately for or primarily on over 75% of any of the following populations? (CHECK ALL THAT APPLY) Children (0-12)... Adolescents (13-17)... Older Adults (=65)... Other (Enter code:,, ). None of the above What was the racial/ethnic breakdown in percent of the population studied? Caucasian... % African Ancestry... % Hispanic... % Asian... % Native American... % Eskimo/Inuit... % Other (enter code):... %... %... %... % Should TOTAL..._1 0 0 Not described

183 16. What was the percent of male participants? (ENTER NUMBER OF 999) % 17. What was reported for the following questions regarding subjects ages? (Enter number 99 for not reported) Mean Age... Median Age... Age Range... to 21. Was there a measure of disease severity reported? (CIRCLE ONE) Yes... 1 No... 2 If yes, what was that measurement(s)? Enter code:,,,,,, 18. What types of covariates are described? (CHECK ALL THAT APPLY) Renal insufficiency... Proteinuria/ nephrotic... Steroid use (daily)... Other... (Enter code:,,, ) None described What were the study s inclusion criteria? (Enter code 99 for not reported) Enter code:,,,,,, 20. What were the study s exclusion criteria? (Enter code 99 for not reported) Enter code:,,,,,, 171

184 Interventions 22. Enter sample size and intervention data for each arm beginning with placebo or control, then in order of first mention: Arm Type Total Is omega 3 Arm Sample size Intervention Components Dose Units quantified? 1 ALA... N ENTERING N COMPLETING ARM TYPE INTERVENTION DHA... EPA... DPA... Not Reported.. 2 ALA... DHA... N ENTERING ARM TYPE EPA... DPA... N COMPLETING INTERVENTION Not Reported.. 3 ALA... DHA... N ENTERING ARM TYPE EPA... DPA... N COMPLETING INTERVENTION Not Reported.. 4 ALA... DHA... N ENTERING ARM TYPE EPA... DPA... N COMPLETING INTERVENTION Not Reported.. 5 ALA... DHA... N ENTERING ARM TYPE EPA... N COMPLETING Enter a number for N entering and N completing or enter 9999 if not reported. INTERVENTION Enter Code Enter code(s) Enter # or 999 for not reported Enter a number 1. g 2. mg 3. oz 4. kcal 5. other DPA... Not Reported.. Enter a number 1.Yes 2.No 8.ND 9.NA Duration of treatment Units Co-intervention(s) Enter a number 998. ND 999. NA Enter a number 1.Hour 2.Day 3.Week 4.Month 5.Year 8.ND 9.NA Enter code(s) 172

185 Interventions (continued) 22. Enter sample size and intervention data for each arm : Arm Type Total Is omega 3 Arm Sample size Intervention Components Dose Units quantified? 6 ALA... N ENTERING N COMPLETING ARM TYPE INTERVENTION DHA... EPA... DPA... Not Reported.. 7 ALA... N ENTERING N COMPLETING ARM TYPE INTERVENTION DHA... EPA... DPA... Not Reported.. 8 ALA... N ENTERING N COMPLETING ARM TYPE INTERVENTION DHA... EPA... DPA... Not Reported.. 9 ALA... N ENTERING N COMPLETING ARM TYPE INTERVENTION DHA... EPA... DPA... Not Reported.. 10 ALA... N ENTERING N COMPLETING Enter a number for N entering and N completing or enter 9999 if not reported. ARM TYPE INTERVENTION Enter Code Enter code(s) Enter # or 999 for not reported Enter a number 1. g 2. mg 3. oz 4. kcal 5. other DHA... EPA... DPA... Not Reported.. Enter a number 1.Yes 2.No 8.ND 9.NA Duration of treatment Units Co-intervention(s) Enter a number 998. ND 999. NA Enter a number 1.Hour 2.Day 3.Week 4.Month 5.Year 8.ND 9.NA Enter code(s) 173

186 RAND EPC, Omega-3 Project Quality Review Form Outcomes 23. Type of outcomes measured: Enter the code for each outcome measured: Evaluation 24. When, relative to the start of the intervention, were outcomes reported? Enter the number and letters in the appropriate box 1 st followup 2 nd followup 3 rd followup 4 th followup 5 th followup 6 th followup Additional follow-ups Number Unit 1. Hour 2. Day 3. Week 4. Month 5. Year 8. ND 9. NA 174

187 RAND EPC, Omega-3 Project Quality Review Form Adverse Events 25. Were any adverse events mentioned? Enter the code for each adverse event or 99 if not reported: 175

188

189 Appendix C. Evidence Tables

190 Table C.1. Evidence table of clinical effect of omega-3 fatty acids in type II diabetes or metabolic syndrome. First Author, Year Study Characteristics Study design Duration Eligibility Criteria Concurrent Disease Condition Medication Alekseeva, Sample size: Age (mean/range): 58 / Race: NR % male: NR Design: RCT Duration: 4 wk Inclusion: Controlled diabetes/hyperlipidemia/ag e Exclusion:NR Covariates: Duration of diabetes/obesity: BMI=27, kg=72.7, lbs=160/hyperlipidemia/hy pertension Arm Interventions Dosage/Duration 1 Low calorie diet 2 Linseed oil 18 g/d X 4 wk # sites: 1 Location: Russia 178

191 Table C.1. Evidence table of clinical effect of omega-3 fatty acids in type II diabetes or metabolic syndrome (continued). First Author, Year Outcomes Results Quality Applicability Funding Source Alekseeva, Total cholesterol (mg/dl at week 4) Arm 1 mean= Arm 2 mean= Mean difference=2.32 (-24.97, 29.60) Reported testing: Article did not report statistical results comparing Arm 1 and Arm 2. Triglyceride (mg/dl at week 4) Arm 1 mean= Arm 2 mean= Mean difference=53.10 (-33.55, ) Reported testing: Article did not report statistical results comparing Arm 1 and Arm 2. Quality: Jadad: 2 Concealment of allocation:nr Applicability: NR Funding source: Government HDL: NR LDL: NR Fasting blood glucose (mg/dl at week 4) Arm 1 mean= Arm 2 mean= Mean difference=9.01 (-24.30, 42.32) Reported testing: Article did not report statistical results comparing Arm 1 and Arm 2. HbA1c: NR 179

192 Table C.1. Evidence table of clinical effect of omega-3 fatty acids in type II diabetes or metabolic syndrome (continued). First Author, Year Study Characteristics Study Design Duration Eligibility Criteria Concurrent Disease Condition Medication Annuzzi, Sample size: 8 Age (mean/range): 51/45-57 Race: NR % male: 100 # sites: 1 Location: Italy Design: RXT Duration: 4 wk X-over: week 8 Run-in: None Wash-out: None Inclusion: Hyperlipidemia/ WHO diabetes criteria Exclusion: Lipid lowering drug use Covariates: Hypoglycemic treatment/duration of diabetes/hb A1c/Obesity: BMI=27, kg=72.7, lbs=160 [Cathy: would just make this into a list as follows, but would have the bullets start further over to the left] Covariates: Hypoglycemic treatment Duration of diabetes/hb A1c Obesity: BMI=27, kg=72.7, lbs=160 Arm Interventions Dosage/Duration 1 Olive oil 10 g/d x 2 wk 2 Max EPA (fish oil) 10 g/d x 2 wk 180

193 Table C.1. Evidence table of clinical effect of omega-3 fatty acids in type II diabetes or metabolic syndrome (continued). First Author, Year Outcomes Results Quality Applicability Funding Source Annuzzi, Total cholesterol (mg/dl at month 0.5) Arm 1 mean= Arm 2 mean= Mean difference=6.18 (-21.65, 34.00) Reported testing: Article reports no significant difference between Arm 1 and Arm 2 by using Wilcoxon s signed rank test. Triglyceride (mg/dl at month 0.5) Arm 1 mean= Arm 2 mean= Mean difference= (-84.26, 18.77) Reported testing: Article reports significant difference (p<0.05) between Arm 1 and Arm 2 by using Wilcoxon s signed rank test. Quality: Jadad: 2 Concealment of allocation: ND Applicability: IIB Funding source: hospital and industry HDL (mg/dl at month 0.5) Arm 1 mean=22.78 Arm 2 mean=22.78 Mean difference=0.00 (-3.21, 3.21) Reported testing: Article reports no significant difference between Arm 1 and Arm 2 by using Wilcoxon s signed rank test. LDL (mg/dl at month 0.5) Arm 1 mean= Arm 2 mean= Mean difference=23.17 (-9.22, 55.56) Reported testing: Article reports s ignificant difference (p<0.025) between Arm 1 and Arm 2 by using Wilcoxon s signed rank test. Fasting blood glucose (mg/dl at month 0.5) Arm 1 mean= Arm 2 mean= Mean difference=-7.93 (-66.18, 50.32) Reported testing: Article reports no significant difference between Arm 1 and Arm 2 by using Wilcoxon s signed rank test. HbA1c: NR 181

194 Table C.1. Evidence table of clinical effect of omega-3 fatty acids in type II diabetes or metabolic syndrome (continued). First Author, Year Study Characteristics Study Design Duration Eligibility Criteria Concurrent Disease Condition Medication Arm Interventions Dosage/Duration Axelrod, Sample size: 20 Age (mean/range): 57 / NR Race: Caucasian, Black % male: NR Design: RCT Duration: 12 wk Inclusion: Age/Controlled diabetes/no weight change in previous 2 or 3 mo./hb A1c < 9.5% or 10.5%/Hb=13 for men, HB=12 for women/retinopathy Covariates: Hypoglycemic treatment/duration of diabetes/hb A1c/Obesity: BMI=27, kg=72.7, lbs=160 1 Safflower oil 5 g/d X 6 wk # sites: 1 Location: US Exclusion: Steroids use/nsaids use/reliable adherence/bleeding disorder/asa use/not moderate or high fish intake/proliferative retinopathy/intraocular hemorrhage 2 Super EPA (fish oil) 5 g/d X 6 wk 182

195 Table C.1. Evidence table of clinical effect of omega-3 fatty acids in type II diabetes or metabolic syndrome (continued). First Author, Year Outcomes Results Quality Applicability Funding Source Axelrod, Total cholesterol (mg/dl at week 6): Arm 1= point estimate not reported Arm 2 = point estimate not reported Meta-analysis: Not performed; point estimates at follow-up not reported. Reported testing: No s ignificant effect (p=0.129) for fish oil (arm 2) using analysis of covariance. Quality: Jadad: 4 Concealment of allocation:yes Applicability: IB LDL (mg/dl at week 6): Arm 1= point estimate not reported Arm 2 = point estimate not reported Meta-analysis: Not performed; point estimates at follow-up not reported. Reported testing: No significant effect for fish oil (arm 2) using analysis of covariance. Funding source: private, nonindustry, hospital HDL (mg/dl at week 6): Arm 1= point estimate not reported Arm 2 = point estimate not reported Meta-analysis: Not performed; point estimates at follow-up not reported. Reported testing: No significant effect for fish oil (arm 2) using analysis of covariance. Triglycerides (mg/dl at week 6): Arm 1= point estimate not reported Arm 2 = point estimate not reported Meta-analysis: Not performed; point estimates at follow-up not reported. Reported testing: Significant (p=0.027) reduction in triglycerides for fish oil using analysis of covariance. HgA1c (% at week 6): Arm 1= point estimate not reported Arm 2 = point estimate not reported Meta-analysis: Not performed; point estimates at follow-up not reported. Reported testing: Significant (p=0.009) increase in HgA1c for fish oil using analysis of covariance. Fasting blood glucose (mg/dl at week 6): Arm 1= point estimate not reported Arm 2 = point estimate not reported Meta-analysis: Not performed; point estimates at follow-up not reported. Reported testing: No significant effect for fish oil (arm 2) using analysis of covariance. 183

196 Table C.1. Evidence table of clinical effect of omega-3 fatty acids in type II diabetes or metabolic syndrome (continued). First Author, Year Study Characteristics Study Design Duration Eligibility Criteria Concurrent Disease Condition Medication Boberg, Sample size: Age (mean/range): 65 / Race: NR % male: 86 # sites: 1 Design: RXT Duration: 16 wk X-over: week 8 Run-in: None Wash-out: None Inclusion: Diet treatment=1 yr Exclusion: Lipid lowering drug use Covariates: Hypoglycemic treatment/duration of diabetes/hb A1c/Obesity: BMI=27, kg=72.7, lbs=160 Arm Interventions Dosage/Duration 1 Olive oil 10 g/d X 8wk 2 Max EPA (fish oil) 10 g/d X 8wk Location: Sweden 184

197 Table C.1. Evidence table of clinical effect of omega-3 fatty acids in type II diabetes or metabolic syndrome (continued). First Author, Outcomes Year Results Boberg, Total cholesterol (mg/dl at week 8): Arm 1= point estimate not reported Arm 2 = point estimate not reported Meta-analysis: Not performed; point estimates before cross-over not reported. Reported testing: No significant difference between groups using analysis of covariance. LDL (mg/dl at week 8): Arm 1= point estimate not reported Arm 2 = point estimate not reported Meta-analysis: Not performed; point estimates before cross-over not reported. Reported testing: Significant (p<0.001) increase in LDL for for fish oil (arm 2) relative to olive oil (arm 1) using analysis of covariance. Quality Applicability Funding Source Quality: Jadad: 3 Concealment of allocation:nr Applicability: IIB Funding source: Government, private, non-industry HDL (mg/dl at week 8): Arm 1= point estimate not reported Arm 2 = point estimate not reported Meta-analysis: Not performed; point estimates before cross-over not reported. Reported testing: : No significant difference between groups using analysis of covariance. Triglycerides (mg/dl at week 8): Arm 1= point estimate not reported Arm 2 = point estimate not reported Meta-analysis: Not performed; point estimates before cross-over not reported. Reported testing: Significant (p< 0.001) reduction in triglycerides for fish oil (arm 2) relative to olive oil (arm 1) using analysis of covariance. HgA1c (% at week 8): Arm 1= point estimate not reported Arm 2 = point estimate not reported Meta-analysis: Not performed; point estimates before cross-over not reported. Reported testing: : No significant difference between groups using analysis of covariance. Fasting blood glucose (mg/dl at week 8): Arm 1= point estimate not reported Arm 2 = point estimate not reported Meta-analysis: Not performed; point estimates before cross-over not reported. Reported testing: : No significant difference between groups using analysis of covariance. 185

198 Table C.1. Evidence table of clinical effect of omega-3 fatty acids in type II diabetes or metabolic syndrome (continued). First Author, Year Study Characteristics Study Design Duration Eligibility Criteria Concurrent Disease Condition Medication Arm Interventions Dosage/Duration Borkman, Sample size: Age (mean/range): 57 / Race: NR % male: 70 Design: RXT Duration: 12 wk X-over: week 9 Run-in: 3 wk Washout: 3 wk Inclusion: NR Exclusion: NR Covariates: Duration of diabetes/obesity: BMI=27, kg=72.7, lbs=160/hypertension 1 Safflower oil 10 g/d X 3 wk 2 Max EPA (fish oil) 10 g/d X 3 wk # sites: 1 Location: Australia 186

199 Table C.1. Evidence table of clinical effect of omega-3 fatty acids in type II diabetes or metabolic syndrome (continued). First Author, Year Outcomes Results Quality Applicability Funding Source Borkman, Total cholesterol (mg/dl at week 6): Arm 1= point estimate not reported Arm 2= point estimate not reported Meta-analysis: Not performed; point estimates before cross-over not reported. Reported testing: Testing between arms not reported. LDL (mg/dl at week 6): Arm 1= point estimate not reported Arm 2 = point estimate not reported Meta-analysis: Not performed; point estimates before cross-over not reported. Reported testing: Testing between arms not reported. Quality: Jadad: 1 Concealment of allocation:nr Applicability: IB Funding source: Government, hospital HDL (mg/dl at week 6): Arm 1= point estimate not reported Arm 2 = point estimate not reported Meta-analysis: Not performed; point estimates before cross-over not reported. Reported testing: Testing between arms not reported. Triglycerides (mg/dl at week 6): Arm 1= point estimate not reported Arm 2 = point estimate not reported Meta-analysis: Not performed; point estimates before cross-over not reported. Reported testing: Testing between arms not reported. HgA1c: NR Fasting blood glucose (mg/dl at week 6): Arm 1= point estimate not reported Arm 2 = point estimate not reported Meta-analysis: Not performed; point estimates before cross-over not reported. Reported testing: Testing between arms not reported. 187

200 Table C.1. Evidence table of clinical effect of omega-3 fatty acids in type II diabetes or metabolic syndrome (continued). First Author, Year Study Characteristics Study Design Duration Eligibility Criteria Concurrent Disease Condition Medication Arm Interventions Dosage/Duration Chan, Sample size: Age (mean/range): 53 / NR Race: NR % male: 100 # sites: 1 Location: Australia Design: RCT Duration: 6 wk Inclusion: Hyperlipidemia/No weight change in previous 2 or 3 mo Exclusion: Lipid lowering drug use/baseline serum creatinine>0.40 mmol/l or >120 mmol/l/not moderate or high fish intake/diabetes/thyroid abnormalities/liver disease/alcohol use Covariates: Hypertension/Obesity: BMI=27, kg=72.7, lbs= Placebo/control Dosage/duration not collected 2 Atorvastatin Dosage/duration not collected 3 Omacor 4 g for 6 wk 4 Omacor plus Atorvastatin 4 g for 6 wk 188

201 Table C.1. Evidence table of clinical effect of omega-3 fatty acids in type II diabetes or metabolic syndrome (continued). First Author, Outcomes Year Results Chan, Total cholesterol (mg/dl at month 1.5) Arm 1 mean= Arm 3 mean= Mean difference= (-36.35, 13.19) Arm 2 mean= Arm 4 mean= Mean difference=11.58 (-9.59, 32.76) Reported testing: Article reports significant Atorvastatin main effect (p=0.001) and nonsignificant Fish main effect based on general linear model. Quality Applicability Funding Source Quality: Jadad: 3 Concealment of allocation:nr Applicability: IIB Funding source: Government, industry, Triglyceride (mg/dl at month 1.5) Arm 1 mean= Arm 3 mean= Mean difference= ( , ) Arm 2 mean= Arm 4 mean= Mean difference= (-52.99, 17.59) Reported testing: Article reports significant Atorvastatin main effect (p=0.002) and Fish main effect (p=0.002) based on general linear model. HDL (mg/dl at month 1.5) Arm 1 mean=39.38 Arm 3 mean=38.61 Mean difference=-0.77 (-6.33, 4.78) Arm 2 mean=40.15 Arm 4 mean=48.26 Mean difference=8.11 (0.63, 15.59) Reported testing: Article reports significant Atorvastatin main effect (p=0.007) and Fish main effect (p=0.041) based on general linear model. LDL (mg/dl at month 1.5) Arm 1 mean= Arm 3 mean= Mean difference=-5.79 (-20.88, 9.29) Arm 2 mean=71.04 Arm 4 mean=83.01 Mean difference=11.97 (-4.51, 28.45) Reported testing: Article reports significant Atorvastatin main effect (p=0.001) and nonsignificant Fish main effect based on general linear model. Fasting blood glucose: NR HbA1c: NR 189

202 Table C.1. Evidence table of clinical effect of omega-3 fatty acids in type II diabetes or metabolic syndrome (continued). First Author, Year Study Characteristics Study Design Duration Eligibility Criteria Concurrent Disease Condition Medication Arm Interventions Dosage/Duration Connor, Sample size: Age (mean/range): 59 / Race: NR % male: 81 # sites: 1 Location: US Design: RXT Duration: 15 mo X-over: month 9 Run-in: 3 mo Washout: None Inclusion: Hyperlipidemia Exclusion: NR Covariates: Hypoglycemic treatment/obesity: BMI=27, kg=72.7, lbs= Olive oil 15 g/d X 6 mo 2 Promega (fish oil) 15 g/d X 6 mo 190

203 Table C.1. Evidence table of clinical effect of omega-3 fatty acids in type II diabetes or metabolic syndrome (continued). First Author, Outcomes Year Results Connor, Total choles terol (mg/dl at month 9): Arm 1= point estimate not reported Arm 2= point estimate not reported Meta-analysis: Not performed; point estimates before cross-over not reported. Reported testing: No significant difference between arms using Wilcoxian signed rank test. LDL (mg/dl at month 9): Arm 1= point estimate not reported Arm 2 = point estimate not reported Meta-analysis: Not performed; point estimates before cross-over not reported. Reported testing: Significant (p=0.0003) difference favoring olive oil (arm 1) using Wilcoxian signed rank test. Quality Applicability Funding Source Quality: Jadad: 2 Concealment of allocation:nr Applicability: IIIB Funding source: Government HDL (mg/dl at month 9): Arm 1= point estimate not reported Arm 2 = point estimate not reported Meta-analysis: Not performed; point estimates before cross-over not reported. Reported testing: No significant difference between arms using Wilcoxian signed rank test. Triglycerides (mg/dl at month 9): Arm 1= point estimate not reported Arm 2 = point estimate not reported Meta-analysis: Not performed; point estimates before cross-over not reported. Reported testing: Significant (p=0.0004) difference favoring fish oil (arm 2) using Wilcoxian signed rank test. HgA1c (% at month 9) Arm 1= point estimate not reported Arm 2 = point estimate not reported Meta-analysis: Not performed; point estimates before cross-over not reported. Reported testing: No significant difference between arms using Wilcoxian signed rank test. Fasting blood glucose (mg/dl at month 9): Arm 1= point estimate not reported Arm 2 = point estimate not reported Meta-analysis: Not performed; point estimates before cross-over not reported. Reported testing: No significant difference between arms using Wilcoxian signed rank test. 191

204 Table C.1. Evidence table of clinical effect of omega-3 fatty acids in type II diabetes or metabolic syndrome (continued). First Author, Year Study Characteristics Study Design Duration Eligibility Criteria Concurrent Disease Condition Medication Arm Interventions Dosage/Duration Dunstan, Sample size: Age (mean/range): 53 / NR Race: NR % male: 76 # sites: 1 Design: RCT Duration: 8 wk Inclusion: Age/Nonsmoker/Hyperlipidemia/Sedentary Exclusion: Lipid lowering drug use/not moderate or high fish intake/proliferative retinopathy/alcohol use/liver disease/renrl disease/neuropathy/cardiovascular disease Covariates: Hypoglycemic treatment/duration of diabetes/obesity: BMI=27, kg=72.7, lbs=160/hb A1c 1 Low-fat and low-sodium diet X 8 wk 2 Low-fat and low-sodium diet X 8 wk 3 Fish Approximately 3.6 g/d of omega-3 fatty acids/d X 8 wk Location: Australia 4 Fish Approximately 3.6 g/d of omega-3 fatty acids/d X 8 wk 192

205 Table C.1. Evidence table of clinical effect of omega-3 fatty acids in type II diabetes or metabolic syndrome (continued). First Author, Outcomes Year Results Quality Applicability Funding Source 193

206 Dunstan, Total cholesterol (mg/dl at month 2) Arm 1 mean= Arm 3 mean= Mean difference= (-46.67, 8.06) Arm 2 mean= Arm 4 mean= Mean difference=7.72 (-19.28, 34.73) Reported testing: Article reports no significant differences based on a generalized linear model or a multiple regression model. Quality: Jadad: 2 Concealment of allocation: NR Applicability: IIB Funding source: Government Triglyceride (mg/dl at month 2) Arm 1 mean= Arm 3 mean= Mean difference= ( , ) Arm 2 mean= Arm 4 mean= Mean difference=-53.1 ( , 26.65) Reported testing: Article reports significant results for a generalized linear model and a multiple regression model. HDL (mg/dl at month 2) Arm 1 mean=29.73 Arm 3 mean=34.36 Mean difference=4.63 (-3.90, 13.16) Arm 2 mean=30.50 Arm 4 mean=30.89 Mean difference=0.39 (-8.03, 8.80) Reported testing: Article reports no significant differences based on a generalized linear model or a multiple regression model. LDL (mg/dl at month 2) Arm 1 mean= Arm 3 mean= Mean difference=5.02 (-21.44, 31.48) Arm 3 mean= Arm 4 mean= Mean difference=19.31 (-6.81, 45.42) Reported testing: Article reports no significant differences based on a generalized linear model or a multiple regression model. Fasting blood glucose (mg/dl at month 2) Arm 1 mean= Arm 3 mean= Mean difference=9.01 (-33.00, 51.02) Arm 2 mean= Arm 4 mean= Mean difference=3.60 (-37.85, 45.06) Reported testing: Article reports significant results for a generalized linear model and a multiple regression model. 194 HbA1c: NR

207 195

208 Table C.1. Evidence table of clinical effect of omega-3 fatty acids in type II diabetes or metabolic syndrome (continued). First Author, Year Study Characteristics Study Design Duration Eligibility Criteria Concurrent Disease Condition Medication Arm Fasching, Sample size: Age (mean/range): 61 / NR Race: NR % male: 40 Design: RXT Duration: 20 wk X-over: week 18 Inclusion: Hyperlipidemia/Controlled diabetes/who diabetes criteria Exclusion: Lipid lowering drug use Covariates: Duration of diabetes/obesity: BMI=27, kg=72.7, lbs=160. Interventions Dosage/Duration 1 Gemfibrozil 4 mmol/d x 2 wk 2 EPAX 5000 (fish oil) 22 mol/d x 2 wk # sites: 1 Location: Australia Run-in: 8 wk Wash-out: 8 wk 196

209 Table C.1. Evidence table of clinical effect of omega-3 fatty acids in type II diabetes or metabolic syndrome (continued). First Author, Year Outcomes Results Quality Applicability Funding Source Fasching, Total cholesterol: (at week 10): Arm 1= point estimate not reported Arm 2= point estimate not reported Meta-analysis: Not performed; point estimates before cross-over not reported. Reported testing: Significant (p=.05) difference between groups, test not specified. LDL: (at week 10): Arm 1= point estimate not reported Arm 2= point estimate not reported Meta-analysis: Not performed; point estimates before cross-over not reported. Reported testing: Significant (p<.02) difference between groups, test not specified. Quality: Jadad: 2 Concealment of allocation: NR Applicability: IB Funding source: Government, hospital HDL: (at week 10): Arm 1= point estimate not reported Arm 2= point estimate not reported Meta-analysis: Not performed; point estimates before cross-over not reported. Reported testing: No significant difference between groups, test not specified. Triglycerides: (at week 10): Arm 1= point estimate not reported Arm 2= point estimate not reported Meta-analysis: Not performed; point estimates before cross-over not reported. Reported testing: Significant (p<.05) difference between groups, test not specified. HgA1c: (at week 10): Arm 1= point estimate not reported Arm 2= point estimate not reported Meta-analysis: Not performed; point estimates before cross-over not reported. Reported testing: No significant difference between groups, test not specified. Fasting blood glucose: (at week 10): Arm 1= point estimate not reported Arm 2= point estim ate not reported Meta-analysis: Not performed; point estimates before cross-over not reported. Reported testing: No significant difference between groups, test not specified. 197

210 Table C.1. Evidence table of clinical effect of omega-3 fatty acids in type II diabetes or metabolic syndrome (continued). First Author, Year Study Characteristics Study Design Duration Eligibility Criteria Concurrent Disease Condition Medication Arm Interventions Dosage/Duration Goh, Sample size: 28 Age (mean/range): 58 / NR Race: NR % male: NR # sites: 1 Design: RXT Duration: 9 mo X-over: month 6 Run-in: 3 mo Wash-out: None Inclusion: Controlled diabetes/hb A1c < 9.5% or 10.5% Exclusion: Lipid lowering drug use Covariates: Hb A1c. 1 Linseed oil Variable dose x 3 mo 2 Fish oil Variable dose x 3 mo Location: Canada 198

211 Table C.1. Evidence table of clinical effect of omega-3 fatty acids in type II diabetes or metabolic syndrome (continued). First Author, Outcomes Year Results Goh, Total cholesterol (mg/dl at month 3): Arm 1= point estimate not reported Arm 2= point estimate not reported Meta-analysis: Not performed; point estimates before cross-over not reported. Reported testing: No significant difference between arms by ANOVA. LDL (mg/dl at month 9): Arm 1= point estimate not reported Arm 2 = point estimate not reported Meta-analysis: Not performed; point estimates before cross-over not reported. Reported testing: Significant (p=0.0003) difference favoring olive oil (arm 1) using Wilcoxian signed rank test. Quality Applicability Funding Source Quality: Jadad: 2 Concealment of allocation: NR Applicability: NR Funding source: Government HDL (mg/dl at month 3): Arm 1= point estimate not reported Arm 2 = point estimate not reported Meta-analysis: Not performed; point estimates before cross-over not reported. Reported testing: No significant difference between arms by ANOVA. Triglycerides (mg/dl at month 3): Arm 1= point estimate not reported Arm 2 = point estimate not reported Meta-analysis: Not performed; point estimates before cross-over not reported. Reported testing: Significant (p=0.05) difference favoring fish oil (arm 2) by ANOVA. HgA1c (% at month 3) Arm 1= point estimate not reported Arm 2 = point estimate not reported Meta-analysis: Not performed; point estimates before cross-over not reported. Reported testing: No significant difference between arms using Wilcoxian signed rank test. HgA1c: NR Fasting blood glucose: NR 199

212 Table C.1. Evidence table of clinical effect of omega-3 fatty acids in type II diabetes or metabolic syndrome (continued). First Author, Year Study Characteristics Study Design Duration Eligibility Criteria Concurrent Disease Condition Medication Arm Interventions Dosage/Duration Hendra, Sample size: Age (mean/range): 56 / NR Race: Caucasian, Black, Asian % male: 69 Design: RCT Duration: 1.5 mo Inclusion: Controlled diabetes/hyperlipidemia Exclusion: PregNRncy/lactating/Cardiovascular disease Covariates: Duration of diabetes/hypertension/hypog lycemic treatment/obesity: BMI=27, kg=72.7, lbs=160 1 Placebo/control Dosage/duration not collected 2 Max EPA (fish oil) 10 g for 6 wk # sites: 1 Location: UK 200

213 Table C.1. Evidence table of clinical effect of omega-3 fatty acids in type II diabetes or metabolic syndrome (continued). First Author, Outcomes Year Results Hendra, Total cholesterol (mg/dl at month 1.5) Arm 1 mean= Arm 2 mean= Mean difference= (-30.89, 7.72) Reported testing: Article reports no significant differences (p=0.7) for changes between Arm 1 and Arm 2 with unpaired Student s t tests. Triglyceride (mg/dl at month 1.5) Arm 1 mean= Arm 2 mean= Mean difference= (-89.80, 1.31) Reported testing: Article reports significant differences (p<0.001) for changes between Arm 1 and Arm 2 with unpaired Student s t tests. Quality Applicability Funding Source Quality: Jadad: 3 Concealment of allocation: NR Applicability: IB Funding source: industry, hospital HDL (mg/dl at month 1.5) Arm 1 mean=46.33 Arm 2 mean=38.61 Mean difference=-7.72 (-14.68, -0.76) Reported testing: Article reports no significant differences (p=0.6) for changes between Arm 1 and Arm 2 with unpaired Student s t tests. LDL (mg/dl at month 1.5) Arm 1 mean= Arm 2 mean= Mean difference=-3.86 (-22.97, 15.25) Reported testing: Article reports no significant differences (p=0.085) for changes between Arm 1 and Arm 2 with unpaired Student s t tests. Fasting blood glucose (mg/dl at month 1.5) Arm 1 mean= Arm 2 mean= Mean difference=21.62 (-18.06, 61.30) Reported testing: Article reports no significant differences (p=0.17) for changes between Arm 1 and Arm 2 with unpaired Student s t tests. HbA1c: NR 201

214 Table C.1. Evidence table of clinical effect of omega-3 fatty acids in type II diabetes or metabolic syndrome (continued). First Author, Year Study Characteristics Study Design Duration Eligibility Criteria Concurrent Disease Condition Medication Arm Hermans 74 Sample size: 20 Age (mean/range): 46 / NR Race: NR % male: NR # sites: 1 Location: Belgium Design: RCT Duration: 2 mo Inclusion: Diabetic nephropathy Exclusion: NR Covariates: Hypoglycemic treatment/hb A1c/Hypertension Interventions Dosage/Duration 1 Placebo/control NR Dosage NR x 2 mo 2 Fish oil 9 g/d x 2 mo 202

215 Table C.1. Evidence table of clinical effect of omega-3 fatty acids in type II diabetes or metabolic syndrome (continued). First Author, Year Outcomes Results Quality Applicability Funding Source Hermans 74 Total cholesterol: NR LDL: NR HDL: NR Triglyceride: (at month 2) Arm 1 = point estimate not reported Arm 2 = point estimate not reported Meta-analysis: Not included; point estimates not reported. Reported testing: Testing between groups not reported. HgA1c: (at month 2) Arm 1 = point estimate not reported Arm 2 = point estimate not reported Meta-analysis: Not included; point estimates not reported. Reported testing: Testing between groups not reported. Fasting blood glucose: NR Quality: Jadad: 2 Concealment of allocation: NR Applicability: NR Funding source: Government 203

216 Table C.1. Evidence table of clinical effect of omega-3 fatty acids in type II diabetes or metabolic syndrome (continued). First Author, Year Study Characteristics Study Design Duration Eligibility Criteria Concurrent Disease Condition Medication Arm Jensen, Sample size: Age (mean/range): 37 / Race: NR % male: 78 # sites: 1 Location: Denmark Design: RXT Duration: 28 wk X-over: week 20 Run-in: 4 wk Wash-out: 8 wk Inclusion: Proteinuria/Retinopathy Exclusion: NR Covariates: Duration of diabetes/hypoglycemic treatment Interventions Dosage/Duration 1 Olive oil 21 ml/d x 8 wk 2 Cod-liver oil (Eskisol) 21 ml/d x 8 wk 204

217 Table C.1. Evidence table of clinical effect of omega-3 fatty acids in type II diabetes or metabolic syndrome (continued). First Author, Year Outcomes Results Jensen, Total cholesterol: (at week 10) Arm 1 = point estimate not reported Arm 2 = point estimate not reported Meta-analysis: Not included; point estimates not reported before crossover. Reported testing: Testing between groups was not significant; either Wilcoxon test for paired differences or paired Student s t-test used. LDL: (at week 10) Arm 1 = point estimate not reported Arm 2 = point estimate not reported Meta-analysis: Not included; point estimates not reported before crossover. Reported testing: Significant (p<.05) difference between groups; either Wilcoxon test for paired differences or paired Student s t-test used. Quality Applicability Funding Source Quality Jadad: 2 Concealment of allocation: NR Applicability: IIB Funding source: Government HDL: (at week 10) Arm 1 = point estimate not reported Arm 2 = point estimate not reported Meta-analys is: Not included; point estimates not reported before crossover. Reported testing: Testing between groups was not significant; either Wilcoxon test for paired differences or paired Student s t-test used. Triglycerides: (at week 10) Arm 1 = point estimate not reported Arm 2 = point estimate not reported Meta-analysis: Not included; point estimates not reported before crossover. Reported testing: Significant (p<.05) difference between groups favoring cod-liver oil; either Wilcoxon test for paired differences or paired Student s t-test used. Change in HgA1c(at week 10) Arm 1 = point estimate not reported Arm 2 = point estimate not reported Meta-analysis: Not included; point estimates not reported before crossover. Reported testing: Statisticaltesting between groups was not reported 205

218 Table C.1. Evidence table of clinical effect of omega-3 fatty acids in type II diabetes or metabolic syndrome (continued). First Author, Year Study Characteristics Study Design Duration Eligibility Criteria Concurrent Disease Condition Medication Arm Luo, Sample size: NR Age (mean/range): 54 / NR Race: NR % male: 10 # sites: 1 Location: Portugal Design: RXT Duration: 6 mo X-over: month 2 Run-in: None Wash-out: 2 mo Inclusion: Hb A1c < 9.5% or 10.5%/Fasting blood glucose Exclusion: ReNRl disease/thyroid abnormalities/liver disease/lipid lowering drug use/gi disorders Covariates: Duration of diabetes/hb A1c/Obesity: BMI=27, kg=72.7, lbs=160/hypoglycemic treatment Interventions Dosage/Duration 1 Sunflower oil 6g/d x 2 mo 2 Fish oil 6 g/d x 2 mo 206

219 Table C.1. Evidence table of clinical effect of omega-3 fatty acids in type II diabetes or metabolic syndrome (continued). First Author, Year Outcomes Results Quality Applicability Funding Source Luo, Total cholesterol: (at month 2) Arm 1 = point estimate not reported Arm 2 = point estimate not reported Meta-analysis: Not included; point estimates not reported before crossover. Reported testing: No treatment effect by ANOVA. LDL: (at month 2) Arm 1 = point estimate not reported Arm 2 = point estimate not reported Meta-analysis: Not included; point estimates not reported before crossover. Reported testing: No treatment effect by ANOVA. Quality: Jadad: 2 Concealment of allocation: Yes Applicability: IIB Funding source: Government, industry HDL: (at month 2) Arm 1 = point estimate not reported Arm 2 = point estimate not reported Meta-analysis: Not included; point estimates not reported before crossover. Reported testing: No treatment effect by ANOVA. Triglycerides: (at month 2) Arm 1 = point estimate not reported Arm 2 = point estimate not reported Meta-analysis: Not included; point estimates not reported before crossover. Reported testing: Significant (p<.05) treatment effect for arm 2 (fish oil) by ANOVA. HgA1c: (at month 2) Arm 1 = point estimate not reported Arm 2 = point estimate not reported Meta-analysis: Not included; point estimates not reported before crossover. Reported testing: No treatment effect by ANOVA. Fasting blood glucose: (at month 2) Arm 1 = point estimate not reported Arm 2 = point estimate not reported Meta-analysis: Not included; point estimates not reported before crossover. Reported testing: No treatment effect by ANOVA. 207

220 Table C.1. Evidence table of clinical effect of omega-3 fatty acids in type II diabetes or metabolic syndrome (continued). First Author, Year Study Characteristics Study Design Duration Eligibility Criteria Concurrent Disease Condition Medication Arm Maffettone, Sample size: Age (mean/range): 56 / NR Race: NR % male: 40 # sites: NR Location: Italy Design: RCT Duration: 6 mo Inclusion: Diabetes type II > 2 years/ elevated triglycerides/age Exclusion: End organ failure/coagulopathy/anticoagulants Covariates: NR Interventions Dosage/Duration 1 Placebo/control Dosage/duration not collected 2 Fish oil 2 g for 6 mo 208

221 Table C.1. Evidence table of clinical effect of omega-3 fatty acids in type II diabetes or metabolic syndrome (continued). First Author, Year Outcomes Results Quality Applicability Funding Source Maffettone, Total cholesterol: NR Triglyceride: NR HDL (mg/dl at month 6) Arm 1 mean=36.68 Arm 2 mean=34.36 MD =-2.32 (-10.69, 6.06) Reported testing: Article reports no significant differences (p>0.05) for changes between Arm 1 and Arm 2. Quality: Jadad: 3 Concealment of allocation: NR Applicability: IIB Funding source: NR LDL (mg/dl at month 6) Arm 1 mean= Arm 2 mean= Mean difference=-0.39 (-47.32, 46.55) Reported testing: Article reports no significant differences (p>0.05) for changes between Arm 1 and Arm 2. Fasting blood glucose: NR HbA1c: NR 209

222 Table C.1. Evidence table of clinical effect of omega-3 fatty acids in type II diabetes or metabolic syndrome (continued). First Author, Year Study Characteristics Study Design Duration Eligibility Criteria Concurrent Disease Condition Medication Arm McGrath, Sample size: Age (mean/range): 53 / Race: NR % male: 87 # sites: 1 Location: UK Design: RXT Duration: 18 wk X-over: week 6 Run-in: None Wash-out: 6 wk Inclusion: NR Exclusion: Cardiovascular disease/hypertension/renrl disease/lipid lowering drug use/antihypertensive meds/cardiovascular drugs Covariates: Obesity: BMI=27, kg=72.7, lbs=160/hypoglycemic treatment/duration of diabetes/hb A1c Interventions Dosage/Duration 1 Olive oil 10g/d x 6 wk 2 Max EPA (fish oil) 10 g/d x 6 wk 210

223 Table C.1. Evidence table of clinical effect of omega-3 fatty acids in type II diabetes or metabolic syndrome (continued). First Author, Year Outcomes Results Quality Applicability Funding Source McGrath, Total cholesterol: (at week 6) Arm 1 = point estimate not reported Arm 2 = point estimate not reported Meta-analysis: Not included; point estimates not reported before crossover. Reported testing: No treatment effect by ANOVA. LDL: (at week 6) Arm 1 = point estimate not reported Arm 2 = point estimate not reported Meta-analysis: Not included; point estimates not reported before crossover. Reported testing: No treatment effect by ANOVA. Quality: Jadad: 3 Concealment of allocation: NR Applicability: IIB Funding source: Government HDL: (at week 6) Arm 1 = point estimate not reported Arm 2 = point estimate not reported Meta-analysis: Not included; point estimates not reported before crossover. Reported testing: No treatment effect by ANOVA. Triglycerides: (at week 6) Arm 1 = point estimate not reported Arm 2 = point estimate not reported Meta-analysis: Not included; point estimates not reported before crossover. Reported testing: No treatment effect by ANOVA. HgA1c: (at week 6) Arm 1 = point estimate not reported Arm 2 = point estimate not reported Meta-analysis: Not included; point estimates not reported before crossover. Reported testing: No treatment effect by ANOVA. Fasting blood glucose: (at week 6) Arm 1 = point estimate not reported Arm 2 = point estimate not reported Meta-analysis: Not included; point estimates not reported before crossover. Reported testing: No treatment effect by ANOVA. 211

224 Table C.1. Evidence table of clinical effect of omega-3 fatty acids in type II diabetes or metabolic syndrome (continued). First Author, Year Study Characteristics Study Design Duration Eligibility Criteria Concurrent Disease Condition Medication Arm Meshcheriak Sample size: 120 ova, Age (mean/range): 55 / Race: NR % male: NR # sites: 1 Location: Russia Design: RCT Duration: 4 wk Inclusion: Controlled diabetes/hyperlipedemia/age Exclusion: NR Covariates: Duration of diabetes/obesity: BMI=27, kg=72.7, lbs=160/hb A1c Interventions Dosage/Duration 1 Low-fat and lowsodium diet 2 Eiconol 8 g for 4 wk 3 Linseed oil 18 g for 4 wk 212

225 Table C.1. Evidence table of clinical effect of omega-3 fatty acids in type II diabetes or metabolic syndrome (continued). First Author, Year Outcomes Results Quality Applicability Funding Source Meshcheriakova, Total cholesterol (mg/dl at week 4) Arm 1 mean= Arm 2 and Arm 3 (combined) mean= Mean difference=4.63 (-15.75, 25.01) Reported testing: Article did not report statistical results comparing Arm 1 and Arm 2. LDL: NR Quality: Jadad: 1 Concealment of allocation: NR Applicability: NR Funding source: Government HDL: NR Triglyceride (mg/dl at week 4) Arm 1 mean= Arm 2 and Arm 3 (combined) mean= Mean difference= (-88.83, 18.03) Reported testing: Article did not report statistical results comparing Arm 1 and Arm 2. HgA1c: NR Fasting blood glucose: NR 213

226 Table C.1. Evidence table of clinical effect of omega-3 fatty acids in type II diabetes or metabolic syndrome (continued). First Author, Year Study Characteristics Study Design Duration Eligibility Criteria Concurrent Disease Condition Medication Arm Morgan, Sample size: Age (mean/range): 54 / NR Race: Caucasian, Black, Hispanic % male: 45 # sites: 1 Location: US Design: RCT Duration: 3.0 mo Inclusion: Hyperlipedemia/Controlled diabetes Exclusion: NR Covariates: Hb A1c/Hypoglycemic treatment/duration of diabetes Interventions Dosage/Duration 1 Placebo/control Dosage/duration not collected 2 Placebo/control Dosage/duration not collected 3 Fish oil 9 g for 12 wk 4 Fish oil 18 g for 12 wk 214

227 Table C.1. Evidence table of clinical effect of omega-3 fatty acids in type II diabetes or metabolic syndrome (continued). First Author, Outcomes Year Results Morgan, Total cholesterol (mg/dl at month 3) Arm 1 mean= Arm 2 mean= Mean difference= (-37.43, 11.18) Reported testing: Article reports no significant differences (p>0.05). Triglyceride (mg/dl at month 3) Arm 1 mean= Arm 2 mean= Mean difference= ( , ) Reported testing: Article reports significant differences (p=0.0001) between Arm 1 and Arm 2. Quality Applicability Funding Source Quality: Jadad: 2 Concealment of allocation: NR Applicability: IB Funding source: Hospital, industry HDL (mg/dl at month 3) Arm 1 mean=35.91 Arm 2 mean=38.61 Mean difference=2.70 (-6.18, 11.58) Reported testing: Article reports no significant differences (p>0.05). LDL (mg/dl at month 3) Arm 1 mean= Arm 2 mean= Mean difference=8.11 (-19.46, 35.67) Reported testing: Article reports no significant differences (p>0.05). Fasting blood glucose (mg/dl at month 3) Arm 1 mean= Arm 2 mean= Mean difference= (-52.95, 24.12) Reported testing: Article reports no significant differences (p>0.05). HbA1c (% at month 3) Arm 1 mean=7.80 Arm 2 mean=7.70 Mean difference=-0.10 (-1.25, 1.05) Reported testing: Article reports no significant differences (p>0.05). 215

228 Table C.1. Evidence table of clinical effect of omega-3 fatty acids in type II diabetes or metabolic syndrome (continued). First Author, Year Study Characteristics Study Design Duration Eligibility Criteria Concurrent Disease Condition Medication Arm Interventions Dosage/Duration Morgan, 67 Sample size: 25 Age (mean/range): 54 / Race: Caucasian, Black, Hispanic % male: 40 # sites: 1 Location: US Design: RCT Duration: 5.3 mo Inclusion: Age/Hyperlipidemia Exclusion: Cardiovascular disease/liver disease/pregnrncy/lactating/renrl disease/thyroid abnormalities/alcohol use/cardiovascular drugs/hormone replacement treatment Covariates: Hypoglycemic treatment/duration of diabetes/obesity: BMI=27, kg=72.7, lbs=160/hyperlipidemia 1 Placebo/control Dosage/duration not collected 2 Placebo/control Dosage/duration not collected 3 Fish oil 18 g for 12 wk 4 Fish oil 9 g for 12 wk 216

229 Table C.1. Evidence table of clinical effect of omega-3 fatty acids in type II diabetes or metabolic syndrome (continued). First Author, Year Outcomes, Results Quality. Applicability Funding Source Morgan, 67 Total cholesterol (mg/dl at week 12) Arm 1 (Low dosage placebo) mean= Arm 3 (Low dosage fish oil) mean= Mean difference= (-96.98, 22.98) Arm 2 (High dosage placebo) mean= Arm 4 (High dosage fish oil) mean= Mean difference=24.00 (-5.75, 53.75) Reported testing: Article reports no significant differences (p>0.05). Triglyceride (mg/dl at week 12) Arm 1 (Low dosage placebo) mean= Arm 2 (Low dosage fish oil) mean= Mean difference= ( , 35.44) Arm 1 (High dosage placebo) mean= Arm 2 (High dosage fish oil) mean= Mean difference=-7.00 ( , 96.19) HDL (mg/dl at week 12) Arm 1 (Low dosage placebo) mean=23.00 Arm 3 (Low dosage fish oil) mean=32.00 Mean difference=9.00 (-3.49, 21.49) Arm 2 (High dosage placebo) mean=37.00 Arm 4 (High dosage fish oil) mean=46.00 Mean difference=9.00 (-13.03, 31.03) Reported testing: Article reports no significant differences (p>0.05). LDL (mg/dl at week 12) Arm 1 (Low dosage placebo) mean= Arm 3 (Low dosage fish oil) mean= Mean difference=8.00 (-52.53, 68.53) Arm 2 (High dosage placebo) mean= Arm 4 (High dosage fish oil) mean= Mean difference=23.00 (-31.39, 77.39) Reported testing: Article reports no significant differences (p>0.05). Fasting blood glucose (mg/dl at week 12) Arm 1 (Low dosage placebo) mean= Arm 2 (Low dosage fish oil) mean= Mean difference= ( , 32.16) Arm 1 (High dosage placebo) mean= Arm 2 (High dosage fish oil) mean= Mean difference= (-89.43, 55.43) Reported testing: Article reports no significant differences (p>0.05). HbA1c (% at week 12) Arm 1 (Low dosage placebo) mean=8.80 Arm 2 (Low dosage fish oil) mean=7.50 Mean difference=-1.30 (-3.42, 0.82) Arm 1 (High dosage placebo) mean=7.30 Arm 2 (High dosage fish oil) mean=8.00 Mean difference=0.70 (-0.68, 2.08) Reported testing: Article reports no significant differences (p>0.05). Quality: Jadad: 4 Concealment of allocation: Yes Applicability: IB Funding source: NR 217

230 Table C.1. Evidence table of clinical effect of omega-3 fatty acids in type II diabetes or metabolic syndrome (continued). First Author, Year Study Characteristics Study Design Duration Eligibility Criteria Concurrent Disease Condition Medication Arm Interventions Dosage/Duration Patti, Sample size: 1006 Age (mean/range): 57 / NR Race: NR % male: 44 # sites: 1 Location: Italy Design: RCT Duration: 6.0 mo Inclusion: Age/WHO diabetes criteria/disease > 1 year/controlled diabetes/no weight change in previous 2 or 3 mo/hyperlipidemia/diet treatment=1 yr/postmenopausal women ± hormone replacement Exclusion: Lipid lowering drug use/antiplatelet or anticoagulation/liver disease/renrl disease/bleeding disorder/proliferative retinopathy/intraocular hemorrhage Covariates: Hb A1c/Obesity: BMI=27, kg=72.7, lbs=160/hypoglycemic treatment/duration of diabetes 1 Placebo/control Dosage/duration not collected 2 Fish oil Variable dose for 6 mo

231 Table C.1. Evidence table of clinical effect of omega-3 fatty acids in type II diabetes or metabolic syndrome (continued). First Author, Year Outcomes Results Quality Applicability Funding Source Patti, Total cholesterol (mg/dl at month 6) Arm 1 mean= Arm 2 mean= Mean difference= (-57.98, 19.37) Reported testing: Article did not report statistical results comparing Arm 1 and Arm 2. Triglyceride (mg/dl at month 6) Arm 1 mean= Arm 2 mean= Mean difference= (-89.24, 50.30) Reported testing: Article did not report statistical results comparing Arm 1 and Arm 2. Quality: Jadad: 2 Concealment of allocation: NR Applicability: IB Funding source: Government, industry HDL (mg/dl at month 6) Arm 1 mean=36.68 Arm 2 mean=34.36 Mean difference=-2.32 (-10.78, 6.14) Reported testing: Article did not report statistical results comparing Arm 1 and Arm 2. LDL: NR Fasting blood glucose (mg/dl at month 6) Arm 1 mean= Arm 2 mean= Mean difference=10.81 (-28.67, 50.29) Reported testing: Article did not report statistical results comparing Arm 1 and Arm 2. HbA1c (% at month 6) Arm 1 mean=7.70 Arm 2 mean=8.30 Mean difference=0.60 (-0.79, 1.99) Reported testing: Article did not report statistical results comparing Arm 1 and Arm

232 Table C.1. Evidence table of clinical effect of omega-3 fatty acids in type II diabetes or metabolic syndrome (continued). First Author, Year Study Characteristics Study Design Duration Eligibility Criteria Concurrent Disease Condition Medication Arm Interventions Dosage/Duration Pelikanova, Sample s ize: Age (mean/range): 52 / Race: NR % male: 100 Design: RCT Duration: 0.8 mo Inclusion: Age/Hyperlipidemia/Controlled diabetes Exclusion: NR Covariates: Hb A1c/Obesity: BMI=27, kg=72.7, lbs=160/malabsortion 1 Placebo/control Dosage/duration not collected 2 Fish oil 15 ml for 3 wk # sites: 1 Location: Czech Republic 220

233 Table C.1. Evidence table of clinical effect of omega-3 fatty acids in type II diabetes or metabolic syndrome (continued). First Author, Year Outcomes Results Quality Applicability Funding Source Pelikanova, Total cholesterol (mg/dl at week 3) Arm 1 mean= Arm 2 mean= Mean difference=18.92 (-12.96, 50.80) Reported testing: Article did not report statistical results comparing Arm 1 and Arm 2. Triglyceride (mg/dl at week 3) Arm 1 mean= Arm 2 mean= Mean difference= ( , 29.33) Reported testing: Article did not report statistical results comparing Arm 1 and Arm 2. Quality: Jadad: 1 Concealment of allocation: NR Applicability: IIB Funding source: Government HDL: NR LDL: NR. Fasting blood glucose: NR HbA1c (% at week 3) Arm 1 mean=7.50 Arm 2 mean=8.40 Mean difference=0.90 (0.02, 1.78) Reported testing: Article reports no significant differences between Arm 1 and Arm

234 Table C.1. Evidence table of clinical effect of omega-3 fatty acids in type II diabetes or metabolic syndrome (continued). First Author, Year Study Characteristics Study Design Duration Eligibility Criteria Concurrent Disease Condition Medication Arm Interventions Dosage/Duration Petersen, Sample size: Age (mean/range): 63 / Race: NR % male: 62 Design: RCT Duration: 2.0 mo Inclusion: Disease > 1 year/hyperlipidemia/diabetes onset at 30 years up/not postmenopausal or hormone replacement Exclusion: Lipid lowering drug use/no fish or fish supplement/alcohol use Covariates: Hypoglycemic treatment/duration of diabetes/hb A1c/Hypertension 1 Placebo/control Dosage/duration not collected 2 Futura 1000 (fish oil) 4 g for 8 wk # sites: 1 Location: Denmark 222

235 Table C.1. Evidence table of clinical effect of omega-3 fatty acids in type II diabetes or metabolic syndrome (continued). First Author, Outcomes Year Results Petersen, Total cholesterol (mg/dl at month 2) Arm 1 mean= Arm 2 mean= Mean difference=16.99 (-5.97, 39.95) Reported testing: Article reports no significant differences (p=0.162) between Arm 1 and Arm 2. Triglyceride (mg/dl at month 2) Arm 1 mean= Arm 2 mean= Mean difference= ( , 14.63) Reported testing: Article reports no significant differences (p=0.105) between Arm 1 and Arm 2. Quality Applicability Funding Source Quality: Jadad: 3 Concealment of allocation: NR Applicability: IB Funding source: government, industry HDL (mg/dl at month 2) Arm 1 mean=42.86 Arm 2 mean=49.42 Mean difference=6.56 (0.13, 13.00) Reported testing: Article reports no significant differences (p=0.062) between Arm 1 and Arm 2. LDL (mg/dl at month 0.5) Arm 1 mean= Arm 2 mean= Mean difference=21.62 (2.79, 40.45) Reported testing: Article reports significant differences (p=0.031) between Arm 1 and Arm 2. Fasting blood glucose: (at month 0.5) Arm 1: point estimate not reported. Arm 2: point estimate not reported. Meta-analysis: Not included; point estimates not reported. Reported testing: Article reports no significant changes. HgA1c: (at month 0.5) Arm 1: point estimate not reported. Arm 2: point estimate not reported. Meta-analysis: Not included; point estimates not reported. Reported testing: Article reports no significant changes. 223

236 Table C.1. Evidence table of clinical effect of omega-3 fatty acids in type II diabetes or metabolic syndrome (continued). First Author, Year Study Characteristics Study Design Duration Eligibility Criteria Concurrent Disease Condition Medication Arm Interventions Dosage/Duration Puhakainen, Sample size: Age (mean/range): 53 / NR Race: NR % male: 44 # sites: 1 Design: RXT Duration: 12 wk X-over: week 6 Run-in: None Wash-out: None Inclusion: NR Exclusion: Cardiovascular disease Covariates: Duration of diabetes/hb A1c/Obesity: BMI=27, kg=72.7, lbs=160/hypoglycemic treatment 1 Corn and olive oils 12 g/d x 6 wk 2 Max EPA (fish oil) 12 g/d x 6 wk Location: Finland 224

237 Table C.1. Evidence table of clinical effect of omega-3 fatty acids in type II diabetes or metabolic syndrome (continued). First Author, Year Outcomes Results Quality Applicability Funding Source Puhakainen, Total cholesterol: (at week 6) Arm 1 = point estimate not reported Arm 2 = point estimate not reported Meta-analysis: Not included; point estimates not reported before crossover. Reported testing: No difference between groups by paired Student s t test. LDL: (at week 6) Arm 1 = point estimate not reported Arm 2 = point estimate not reported Meta-analysis: Not included; point estimates not reported before crossover. Reported testing: No difference between groups by paired Student s t test. Quality: Jadad: 2 Concealment of allocation: NR Applicability: IB Funding source: Government HDL: (at week 6) Arm 1 = point estimate not reported Arm 2 = point estimate not reported Meta-analysis: Not included; point estimates not reported before crossover. Reported testing: No difference between groups by paired Student s t test. Triglycerides: (at week 6) Arm 1 = point estimate not reported Arm 2 = point estimate not reported Meta-analysis: Not included; point estimates not reported before crossover. Reported testing: Significant (p<.05) difference between groups favoring fish oil by Student s t test. HgA1c: (at week 6) Arm 1 = point estimate not reported Arm 2 = point estimate not reported Meta-analysis: Not included; point estimates not reported before crossover. Reported testing: Reported testing: No difference between groups by paired Student s t test. Fasting blood glucose: (at week 6) Arm 1 = point estimate not reported Arm 2 = point estimate not reported Meta-analysis: Not included; point estimates not reported before crossover. Reported testing: Reported testing: No difference between groups by paired Student s t test. 225

238 Table C.1. Evidence table of clinical effect of omega-3 fatty acids in type II diabetes or metabolic syndrome (continued). First Author, Year Study Characteristics Study Design Duration Eligibility Criteria Concurrent Disease Condition Medication Arm Interventions Dosage/Duration Rivellese, Sample size: Age (mean/range): 57 / NR Race: NR % male: 44 # sites: 1 Location: Italy Design: RCT Duration: 6 mo Inclusion: WHO diabetes criteria/controlled diabetes/diet treatment=1 yr/no weight change in previous 2 or 3 mo/hyperlipidemia/age/postmenopausal women ± hormone replacement/disease > 1 year Exclusion: Intraocular hemorrhage/liver disease/renrl disease/bleeding disorder/proliferative retinopathy/antiplatelet or anticoagulation/lipid lowering drug use Covariates: Hypoglycemic treatment/duration of diabetes/hb A1c/Obesity: BMI=27, kg=72.7, lbs=160 1 Olive oil Variable dose x 6 mo 2 Fish oil Variable dose x 6 mo 226

239 Table C.1. Evidence table of clinical effect of omega-3 fatty acids in type II diabetes or metabolic syndrome (continued). First Author, Year Outcomes Results Rivellese, Total cholesterol: (mmol/l at month 6) Arm 1= point estimate not reported Arm 2= 5.7 mmol/l Meta-analysis: Not included; point estimate for Arm 1 not reported. Reported testing: Testing between arms was not reported. LDL (mg/dl at month 6) Arm 1 mean= Arm 2 mean= Mean difference=-0.39 (-47.31, 46.54) Reported testing: Article reports no significant differences (p>0.05) for changes between Arm 1 and Arm 2. Quality Applicability Funding Source Quality: Jadad: 2 Concealment of allocation: NR Applicability: IB Funding source: Government, industry HDL: (mmol/l at month 6) Arm 1= 0.25 Arm 2= 0.19 Meta-analysis: Not included. Reported testing: No significant difference between groups using paired Student s t test. Triglycerides: Not reported Note: triglyceride contend of specific lipoproteins was reported, but not total serum triglycerides. HgA1c: (%at month 6) Arm 1 = 6.9 Arm 2 = 8.3 Meta-analys is: Not included. Reported testing: No difference between groups by paired Student s t test. Fasting blood glucose: (mmol/l at month 6) Arm 1 = 10.3 Arm 2 = 10.9 Meta-analysis: Not included. Reported testing: No difference between groups by paired Student s t test. 227

240 Table C.1. Evidence table of clinical effect of omega-3 fatty acids in type II diabetes or metabolic syndrome (continued). First Author, Year Study Characteristics Study Design Duration Eligibility Criteria Concurrent Disease Condition Medication Arm Interventions Dosage/Duration Sarkkinen, Sample size: Age (mean/range): 56 / NR Race: NR % male: 59 Design: RCT Duration: 2.0 mo Inclusion: WHO diabetes criteria/who impaired glucose tolerance criteria Exclusion: NR Covariates: NR 1 Sunflower oil Dosage/duration not collected 2 Rapeseed (LEAR) oil Dosage/duration NR # sites: 1 Location: Finland 228

241 Table C.1. Evidence table of clinical effect of omega-3 fatty acids in type II diabetes or metabolic syndrome (continued). First Author, Year Outcomes Results Quality Applicability Funding Source Sarkkinen, Total cholesterol (mg/dl at month 2) Arm 1 mean= Arm 2 mean= Mean difference= (-45.21, 9.69) Reported testing: Article did not report statistical results comparing Arm 1 and Arm 2. Triglyceride (mg/dl at month 2) Arm 1 mean= Arm 2 mean= Mean difference= (-80.05, 34.03) Reported testing: Article did not report statistical results comparing Arm 1 and Arm 2. Quality: Jadad: 1 Concealment of allocation: NR Applicability: IB Funding source: Government HDL (mg/dl at month 2) Arm 1 mean=49.03 Arm 2 mean=45.94 Mean difference=-3.09 (-9.84, 3.67) Reported testing: Article did not report statistical results comparing Arm 1 and Arm 2. LDL (mg/dl at month 2) Arm 1 mean= Arm 2 mean= Mean difference= (-37.38, 17.30) Reported testing: Article did not report statistical results comparing Arm 1 and Arm 2. Fasting blood glucose: (mg/dl at month 2) Arm 1 = point estimate not reported. Arm 2 = point estimate not reported. Meta-analysis: Not included; point estimates not reported. Reported testing: No significant difference between Arm 1 and Arm 2 using Students t test. HgA1c: NR 229

242 Table C.1. Evidence table of clinical effect of omega-3 fatty acids in type II diabetes or metabolic syndrome (continued). First Author, Year Study Characteristics Study Design Duration Eligibility Criteria Concurrent Disease Condition Medication Arm Interventions Dosage/Duration Schectman, Sample size: Age (mean/range): 52 / Race: NR % male: 69 # sites: 1 Design: RXT Duration: 15 wk X-over: week 11 Run-in: 3 wk Wash-out: 4 wk Inclusion: Hyperlipidemia/Diet treatment=1 yr/controlled diabetes Exclusion: Liver disease/renrl disease/thyroid abnormalities/diabetes/lipid lowering drug use/no fish or fish supplement Covariates: Obesity: BMI=27, kg=72.7, lbs=160/hyperlipidemia/hypogl ycemic treatment/hypertension 1 Safflower oil 12g/d x 4 wk 2 Max EPA (fish oil) 12 g/d x 4 wk Location: US 230

243 Table C.1. Evidence table of clinical effect of omega-3 fatty acids in type II diabetes or metabolic syndrome (continued). First Author, Year Outcomes Results Quality Applicability Funding Source Schectman, Total cholesterol: (at week 7) Arms 1, 2 = point estimates not reported. Meta-analysis: Not included; point estimates before cross over not reported. Reported testing: A tendency towards an increase with fish oil by ANOVA (p<0.05). LDL: (at week 7) Arms 1, 2 = point estimates not reported. Meta-analysis: Not included; point estimates before cross over not reported. Reported testing: A tendency towards an increase with fish oil by ANOVA (p<0.05). Quality: Jadad: 2 Concealment of allocation: NR Applicability: IB Funding source: Government HDL: (at week 7) Arms 1, 2 = point estimates not reported. Meta-analysis: Not included; point estimates before cross over not reported. Reported testing: No significant treatment effect by ANOVA. Change in Triglycerides: (at week 7) Arms 1, 2 = point estimates not reported. Meta-analysis: Not included; point estimates before cross over not reported. Reported testing: A tendency towards an increase with fish oil by ANOVA (p<0.05). Fasting blood glucose: (at week 7) Arms 1, 2 = point estimates not reported. Meta-analysis: Not included; point estimates before cross over not reported. Reported testing: A tendency towards an increase with fish oil by ANOVA (p<0.05). HgA1c. (at week 7) Arms 1, 2 = point estimates not reported. Meta-analysis: Not included; point estimates before cross over not reported. Reported testing: No significant treatment effect by ANOVA. 231

244 Table C.1. Evidence table of clinical effect of omega-3 fatty acids in type II diabetes or metabolic syndrome (continued). First Author, Year Study Characteristics Study Design Duration Eligibility Criteria Concurrent Disease Condition Medication Arm Interventions Dosage/Duration Schwab, Sample size: Age (mean/range): 56 / Race: NR % male: 59 Design: RCT Duration: 8 wk Inclusion: WHO diabetes criteria/who impaired glucose tolerance criteria Exclusion: NR Covariates: Obesity: BMI=27, kg=72.7, lbs=160/hypertension 1 Sunflower oil Dosage NR x 8 wk 2 Rapeseed (LEAR) oil Dosage NR x 8 wk # sites: 1 Location: Finland 232

245 Table C.1. Evidence table of clinical effect of omega-3 fatty acids in type II diabetes or metabolic syndrome (continued). First Author, Year Outcomes Results Quality Applicability Funding Source Schwab, Total cholesterol: (at week 8) Arms 1, 2 = point estimates not reported. Meta-analysis: Not included; point estimates before cross over not reported. Reported testing: No significant difference between groups by paired Student s t test. LDL: (at week 8) Arms 1, 2 = point estimates not reported. Meta-analysis: Not included; point estimates before cross over not reported. Reported testing: No significant difference between groups by paired Student s t test. Quality: Jadad: 1 Concealment of allocation: NR Applicability: IB Funding source: Government, nonindustry, private HDL: (at week 8) Arms 1, 2 = point estimates not reported. Meta-analysis: Not included; point estimates before cross over not reported. Reported testing: No significant difference between groups by paired Student s t test. Change in Triglycerides: (at week 8) Arms 1, 2 = point estimates not reported. Meta-analysis: Not included; point estimates before cross over not reported. Reported testing: No significant difference between groups by paired Student s t test. Fasting blood glucose: NR HgA1c. NR 233

246 Table C.1. Evidence table of clinical effect of omega-3 fatty acids in type II diabetes or metabolic syndrome (continued). First Author, Year Study Characteristics Study Design Duration Eligibility Criteria Concurrent Disease Condition Medication Arm Interventions Dosage/Duration Shimizu, Sample size: Age (mean/range): 63 / NR Race: NR % male: 49 Design: RCT Duration: 12 mo Inclusion: Normal BUN/Normal serum creatinine Exclusion: NR Covariates: Hypertension/Hypoglycemic treatment/duration of diabetes 1 Placebo/control Dosage/duration not collected 2 EPA-E 900 mg for 12 hr # sites: 1 Location: Japan 234

247 Table C.1. Evidence table of clinical effect of omega-3 fatty acids in type II diabetes or metabolic syndrome (continued). First Author, Year Outcomes Results Quality Applicability Funding Source Shimizu, Total cholesterol (mg/dl at month 12) Arm 1 mean= Arm 2 mean= Mean difference=12.40 (-2.30, 27.10) Reported testing: Article did not report statistical results comparing Arm 1 and Arm 2. Triglyceride (mg/dl at month 12) Arm 1 mean= Arm 2 mean= Mean difference=30.40 (-23.37, 84.17) Reported testing: Article did not report statistical results comparing Arm 1 and Arm 2. Quality: Jadad: 1 Concealment of allocation: NR Applicability: IB Funding source: unclear HDL (mg/dl at month 12) Arm 1 mean=50.00 Arm 2 mean=55.80 Mean difference=5.80 (-2.70, 14.30) Reported testing: Article did not report statistical results comparing Arm 1 and Arm 2. LDL: NR Fasting blood glucose: NR HbA1c (% at month 12) Arm 1 mean=7.76 Arm 2 mean=7.82 Mean difference=0.06(-8.44, 8.56) Reported testing: Article did not report statistical results comparing Arm 1 and Arm

248 Table C.1. Evidence table of clinical effect of omega-3 fatty acids in type II diabetes or metabolic syndrome (continued). First Author, Year Study Characteristics Study Design Duration Eligibility Criteria Concurrent Disease Condition Medication Arm Interventions Dosage/Duration Sirtori, Sample size: Age (mean/range): 59 / NR Race: NR % male: 62 # sites: 63 Design: RCT Duration: 6 mo Inclusion: Age/Hyperlipidemia/Disease > 1 year/controlled diabetes Exclusion: ReNRl disease/lipid lowering drug use/cardiovascular disease/reliable adherence/alcohol use/cardiovascular drugs/insulin treatment/obesity Covariates: Obesity: BMI=27, kg=72.7, lbs= Olive oil Variable dose x 6 mo 2 Esapent (fish oil) Variable dose x 6 mo Location: Italy 236

249 Table C.1. Evidence table of clinical effect of omega-3 fatty acids in type II diabetes or metabolic syndrome (continued). First Author, Year Outcomes Results Quality Applicability Funding Source Sirtori, Total cholesterol: (at month 6) Arms 1, 2 = point estimates not reported. Meta-analysis: Not included; point estimates not reported; graphical data only. Reported testing: No difference between arms by ANOVA. LDL: (at month 6) Arms 1, 2 = point estimates not reported. Meta-analysis: Not included; point estimates not reported; graphical data only. Reported testing: Significant (p<.048) difference between arms with higher LDL in fish oil arm by ANOVA. Quality: Jadad: 4 Concealment of allocation: NR Applicability: IB Funding source: Government HDL: (at month 6) Arms 1, 2 = point estimates not reported. Meta-analysis: Not included; point estimates not reported; graphical data only. Reported testing: No difference between arms by ANOVA. Change in Triglycerides: (at month 6) Arms 1, 2 = point estimates not reported. Meta-analysis: Not included; point estimates not reported; graphical data only. Reported testing: Significant (p<.0001) difference between arms with lower triglyceride in fish oil arm by ANOVA. Fasting blood glucose: : (at month 6) Arms 1, 2 = point estimates not reported. Meta-analysis: Not included; point estimates not reported; graphical data only. Reported testing: No difference between arms by ANOVA. HgA1c. : (at month 6) Arms 1, 2 = point estimates not reported. Meta-analysis: Not included; point estimates not reported; graphical data only. Reported testing: No difference between arms by ANOVA. 237

250 Table C.1. Evidence table of clinical effect of omega-3 fatty acids in type II diabetes or metabolic syndrome (continued). First Author, Year Study Characteristics Study Design Duration Eligibility Criteria Concurrent Disease Condition Medication Arm Interventions Dosage/Duration Sirtori, Sample size: Age (mean/range): 59 / NR Race: NR % male: 62 # sites: 63 Design: RCT Duration: 12 mo Inclusion: Hyperlipidemia/Age/Disease > 1 year/controlled diabetes Exclusion: Lipid lowering drug use/reliable adherence/renrl disease/alcohol use/cardiovascular disease/cardiovascular drugs/insulin treatment/obesity Covariates: Obesity: BMI=27, kg=72.7, lbs=160 1 Olive oil Variable dose x 12 mo 2 Esapent (fish oil) Variable dose for 12 mo Location: Italy 238

251 Table C.1. Evidence table of clinical effect of omega-3 fatty acids in type II diabetes or metabolic syndrome (continued). First Author, Outcomes Year Results Sirtori, Total cholesterol (change from graph data mg/dl at month 6): Arm 1: +0.5 Arm 2: -1.0 Meta-analysis: Not included; point estimates not reported; graphical data only. Reported testing: No significant difference between groups using repeated measures ANOVA. LDL(change mg/dl at month 6) : Arm 1: point estimate not reported Arm 2: Meta-analysis: Not included; point estimates not reported; graphical data only. Reported testing: Borderline significant (p=0.046) between fish oil (Arm 1) and olive oil (Arm 2) using repeated measures ANOVA. Quality Applicability Funding Source Quality: Jadad: 3 Concealment of allocation: NR Applicability: IB Comments: Meta-analysis performed on HgA1c and fasting blood glucose. Funding source: Government HDL (% change mg/dl at month 6): Arm 1: + 5% Arm 2: + 5% Meta-analysis: Not included; point estimates not reported. Reported testing: No significant difference between groups using repeated measures ANOVA. Triglycerides(change from graph data mg/dl at month 6): Arm 1: -20 Arm 2: -62 Meta-analysis: Not included; point estimates not reported; graphical data only. Reported testing: Significant (P<0.0001) difference between fish oil (Arm 1) and olive oil (Arm 2) using repeated measures ANOVA. Fasting blood glucose (mg/dl at month 6) Arm 1 mean= Arm 2 mean= Mean difference=4.30 (-2.82, 11.42) Reported testing: Article reports no significant differences (p>0.05) between Arm 1 and Arm 2. HbA1c (% at month 6) Arm 1 mean=6.88 Arm 2 mean=7.05 Mean difference=0.17 (-0.12, 0.46) Reported testing: Article reports no significant differences (p>0.05) between Arm 1 and Arm

252 Table C.1. Evidence table of clinical effect of omega-3 fatty acids in type II diabetes or metabolic syndrome (continued). First Author, Year Study Characteristics Study Design Duration Eligibility Criteria Concurrent Disease Condition Medication Arm Interventions Dosage/Duration Vandongen, Sample size: Age (mean/range): 32 / Race: NR % male: 100 Design: CCT Duration: 9 wk Inclusion: Hyperlipidemia/Age Exclusion: NR Covariates: Duration of diabetes/obesity: BMI=27, kg=72.7, lbs=160/hypoglycemic treatment 1 Usual diet X 3 wk 2 Max EPA (fish oil) 15 g/d x 3 wk # sites: 1 Location: Australia 240

253 Table C.1. Evidence table of clinical effect of omega-3 fatty acids in type II diabetes or metabolic syndrome (continued). First Author, Year Outcomes Results Quality Applicability Funding Source Vandongen, Total cholesterol (at week 9): Arm 1 = point estimate not reported Arm 2 = point estimate not reported Meta-analysis: Not included; point estimates not reported. Reported testing: Testing between groups not reported. HDL (at week 9): Arm 1 = point estimate not reported Arm 2 = point estimate not reported Meta-analysis: Not included; point estimates not reported. Reported testing: Testing between groups not reported. Quality: Jadad: 0 Concealment of allocation: NR Applicability: IIB Funding source: government LDL (at week 9): Arm 1 = point estimate not reported Arm 2 = point estimate not reported Meta-analysis: Not included; point estimates not reported. Reported testing: Testing between groups not reported. Triglycerides (at week 9): Arm 1 = point estimate not reported Arm 2 = point estimate not reported Meta-analysis: Not included; point estimates not reported. Reported testing: Testing between groups not reported. HgA1c (at week 9): Arm 1 = point estimate not reported Arm 2 = point estimate not reported Meta-analysis: Not included; point estimates not reported. Reported testing: Testing between groups not reported. Fasting blood glucose (at week 9): Arm 1 = point estimate not reported Arm 2 = point estimate not reported Meta-analysis: Not included; point estimates not reported. Reported testing: Testing between groups not reported. 241

254 Table C.1. Evidence table of clinical effect of omega-3 fatty acids in type II diabetes or metabolic syndrome (continued). First Author, Year Study Characteristics Study Design Duration Eligibility Criteria Concurrent Disease Condition Medication Arm Interventions Dosage/Duration Vessby, Sample size: Age (mean/range): NR / Race: NR % male: 79 # sites: 1 Design: RXT Duration: 16 wk X-over: week 8 Run-in: None Wash-out: None Inclusion: Diet treatment=1 yr/controlled diabetes Exclusion: Lipid lowering drug use Covariates: NR 1 Olive oil 10 g/d x 8 wk 2 Max EPA (fish oil) 10 g/d x 8 wk Location: Sweden 242

255 Table C.1. Evidence table of clinical effect of omega-3 fatty acids in type II diabetes or metabolic syndrome (continued). First Author, Year Outcomes Results Quality Applicability Funding Source Vessby, Total cholesterol (at week 8): Arm 1= point estimate not reported Arm 2= point estimate not reported Meta-analysis: Not performed; point estimates before cross-over not reported. Reported testing: No significant difference between arms using analysis of variance. LDL(at week 8): Arm 1= point estimate not reported Arm 2= point estimate not reported Meta-analysis: Not performed; point estimates before cross-over not reported. Reported testing: No significant difference between arms using analysis of variance. Quality: Jadad: 3 Concealment of allocation: NR Applicability: IIB Funding source: Government, nonindustry, private HDL(at week 8): Arm 1= point estimate not reported Arm 2= point estimate not reported Meta-analysis: Not performed; point estimates before cross-over not reported. Reported testing: No significant difference between arms using analysis of variance. Triglycerides(at week 8): Arm 1= point estimate not reported Arm 2= point estimate not reported Meta-analysis: Not performed; point estimates before cross-over not reported. Reported testing: No significant difference between arms using analysis of variance. HgA1c(at week 8): Arm 1= point estimate not reported Arm 2= point estimate not reported Meta-analysis: Not performed; point estimates before cross-over not reported. Reported testing: No significant difference between arms using analysis of variance. Fasting blood glucose(at week 8): Arm 1= point estimate not reported Arm 2= point estimate not reported Meta-analysis: Not performed; point estimates before cross-over not reported. Reported testing: Significant (p=0.007) difference between fish oil (Arm 1) and olive oil (Arm 2) using analysis of variance. 243

256 Table C.1. Evidence table of clinical effect of omega-3 fatty acids in type II diabetes or metabolic syndrome (continued). First Author, Year Study Characteristics Study Design Duration Eligibility Criteria Concurrent Disease Condition Medication Arm Interventions Dosage/Duration Westerveld, Sample size: Age (mean/range): 57 / Race: NR % male: 63 # sites: 1 Location: Netherlands Design: RCT Duration: 8 wk Inclusion: WHO diabetes criteria/clinically stable/diet treatment=1 yr Exclusion: Cardiovascular disease/lipid lowering drug use/no fish or fish supplement/gi disorders/liver disease/renrl disease/bleeding disorder/antiplatelet or anticoagulation Covariates: Duration of diabetes/hypoglycemic treatment/hb A1c/Obesity: BMI=27, kg=72.7, lbs=160 1 Olive oil 1656 mg/d x 8 wk 2 EPA-E 1800 mg/d x 8 wk 3 EPA-E 900 mg/d x 8 wk 244

257 Table C.1. Evidence table of clinical effect of omega-3 fatty acids in type II diabetes or metabolic syndrome (continued). First Author, Year Outcomes Results Quality Applicability Funding Source Westerveld, Total cholesterol (at week 8): Arm 1= point estimate not reported Arm 2= point estimate not reported Arm 3= point estim ate not reported Meta-analysis: Not performed; point estimates not reported. Reported testing: No significant difference between arms using repeated measures ANOVA. LDL (at week 8): Arm 1= point estimate not reported Arm 2= point estimate not reported Arm 3= point estimate not reported Meta-analysis: Not performed; point estimates not reported. Reported testing: No significant difference between arms using repeated measures ANOVA. Quality: Jadad: 4 Concealment of allocation: NR Applicability: IB Funding source: Government HDL(at week 8): Arm 1= point estimate not reported Arm 2= point estimate not reported Arm 3= point estimate not reported Meta-analysis: Not performed; point estimates not reported. Reported testing: No significant difference between arms using repeated measures ANOVA. Triglyceride (at week 8): Arm 1= point estimate not reported Arm 2= point estimate not reported Arm 3= point estimate not reported Meta-analysis: Not performed; point estimates not reported. Reported testing: No significant difference between arms using repeated measures ANOVA. HbA1c (% at month 2) Arm 1 mean=9.30 Arm 2 and Arm 3 (combined) mean=8.00 Mean difference=-1.30 (-3.55, 0.95) Reported testing: Article did not report statistical results comparing Arm 1 and Arm 2 and Arm 3. Fasting blood glucose (at week 8): Arm 1= point estimate not reported Arm 2= point estimate not reported Arm 3= point estimate not reported Meta-analysis: Not performed; point estimates not reported. Reported testing: No significant difference between arms using repeated measures ANOVA. 245

258 Table C.1. Evidence table of clinical effect of omega-3 fatty acids in type II diabetes or metabolic syndrome (continued). First Author, Year Study Characteristics Study Design Duration Eligibility Criteria Concurrent Disease Condition Medication Arm Interventions Dosage/Duration Woodman, Sample size: Age (mean/range): 61 / NR Race: NR Design: RCT Duration: 1.5 mo Inclusion: Hyperlipidemia/Age/Hb A1c < 9.5% or 10.5%/Controlled diabetes/nonsmoker/clinically stable/fasting blood glucose/not on insulin treatment Covariates: Duration of diabetes/hb A1c/Obesity: BMI=27, kg=72.7, lbs=160/ 0 1 Placebo/control Dosage/duration not collected % male: 77 # sites: 1 Location: Australia Exclusion: NSAIDs use/liver disease/renrl disease/cardiovascular disease/not moderate or high fish intake/microproteinuria/neuropathy/s moking 2 EPA 4 g for 6 wk 3 DHA 4 g for 6 wk 246

259 Table C.1. Evidence table of clinical effect of omega-3 fatty acids in type II diabetes or metabolic syndrome (continued). First Author, Outcomes Year Results Quality Applicability Funding Source Woodman, Total cholesterol (mg/dl at week 6) Arm 1 mean= Arm 2 and Arm 3 (combined) mean= Mean difference=-4.75 (-22.48, 12.97) Reported testing: Article reports no significant EPA effect (p>0.05) and DHA effect (p>0.05) without adjusting baseline value by using the Bonferroni method. Triglyceride (mg/dl at week 6) Arm 1 mean= Arm 2 and Arm 3 (combined) mean= Mean difference= (-68.98, ) Reported testing: Article reports significant EPA effect (p<0.05) and DHA effect (p<0.05) without adjusting baseline value by using the Bonferroni method. Quality: Jadad: 3 Concealment of allocation: NR Applicability: IIB Funding source: Government HDL (mg/dl at week 6) Arm 1 mean=41.31 Arm 2 and Arm 3 (combined) mean=43.33 Mean difference=2.02 (-4.44, 8.48) Reported testing: Article reports no significant EPA effect (p>0.05) and DHA effect (p>0.05) without adjusting baseline value by using the Bonferroni method. LDL (mg/dl at week 6) Arm 1 mean= Arm 2 and Arm 3 (combined) mean= Mean difference=0.50 (-13.80, 14.79) Reported testing: Article reports no significant EPA effect (p>0.05) and DHA effect (p>0.05) without adjusting baseline value by using the Bonferroni method. Fasting blood glucose (mg/dl at week 6) Arm 1 mean= Arm 2 and Arm 3 (combined) mean= Mean difference=19.81 (2.25, 37.37) Reported testing: Article reports significant EPA effect (p=0.002) and DHA effect (p=0.002) after adjustment for baseline value by using the Bonferroni method. HbA1c (% at week 6) Arm 1 mean=7.04 Arm 2 and Arm 3 (combined) mean=7.27 Mean difference=0.23 (-0.28, 0.75) Reported testing: Article reports no significant EPA effect (p>0.05) and DHA effect (p>0.05) after adjustment for baseline value by using the Bonferroni method. 247

260 Table C.2. Evidence table of clinical effect of omega-3 fatty acids in inflammatory bowel disease. First Author, Year Study Characteristics Study Design Duration Eligibility Criteria Concurrent Disease Condition Medication Arm Interventions Dosage/Duration Almallah YZ, Sample size: Age (mean/range): NA / Race: NA % male: 50 # sites: NA Design: RCT Duration: 6 mo Inclusion: Biopsy-proven ulcerative colitis/distal disease Exclusion: Steroid treatment/pregnancy/ Immune disorder Covariates: Sulphasalazine or mesalazine 1 Sunflower oil 15 ml/d x 6 mo (SASP)/Rectal steroids 2 Fish oil 15 ml/d x 6 mo Location: UK

261 Table C.2. Evidence table of clinical effect and association of omega-3 fatty acids with inflammatory bowel disease (continued). First Author, Year Outcomes Results Quality Applicability Funding Source Almallah YZ, Clinical score (change at month 6): Arm 1= -2 Arm 2 = -5 Meta-anlysis: Not done; too few studies to pool. Reported testing: Testing between arms not reported. Quality: Jadad: 2 Concealment of allocation: Yes Applicability: IB Sigmoidoscopic score (change at month 6): Arm 1= -5 Arm 2 = -9 Meta-anlysis: Not done; too few studies to pool. Reported testing: Significant (p = 0.013) effect for fish oil (Arm 2) relative to sunflower oil (Arm 1) using Mann-Whitney U test. Funding source: Hospital Histological score (change at month 6): Arm 1= -2 Arm 2 = -4 Meta-anlysis: Not done; too few studies to pool. Reported testing: Significant (p = 0.016) effect for fish oil (Arm 2) relative to sunflower oil (Arm 1) using Mann-Whitney U test. Induced remission(rate at month 6): Arm 1= point estimate not reported Arm 2 = 100% Meta-anlysis: Not done; too few studies to pool. Reported testing: Testing between arms not reported. Relapse: NA Immunosupressive requirement (# of patients at month 6, prednisolone enemata/oral corticosteroids): Arm 1 = 4/3 Arm 2 = 2/0 Meta-anlysis: Not done; too few studies to pool. Reported testing: Testing between arms not reported. 249

262 Table C.2. Evidence table of clinical effect and association of omega-3 fatty acids with inflammatory bowel disease (continued). First Author, Year Study Characteristics Study Design Duration Eligibility Criteria Concurrent Disease Condition Medication Arm Interventions Dosage/Duration Aslan A, Sample size: 11 Age (mean/range): 63 / Race: NR % male: 100 Design: RXT Duration: 3 mo X-over: month 3 Run-in: None Wash-out: 2 mo Inclusion: Mild to moderate IBD with min 10 cm/biopsy-proven ulcerative colitis Exclusion: NR Covariates: Sulphasalazine or mesalazine (SASP)/Rectal 1 Oleic, palmitic, and linoleic acids 15 cap/d x 3 mo steroids 2 Max EPA (fish oil) 15 cap/d x 3 mo # sites: 1 Location: US 250

263 Table C.2. Evidence table of clinical effect and association of omega-3 fatty acids with inflammatory bowel disease (continued). First Author, Year Outcomes Results Quality Applicability Funding Source Aslan A, Clinical score (change at month 3): Arm 1= point estimate before cross-over not reported Arm 2 = point estimate before cross-over not reported Meta-anlysis: Not done; too few studies to pool. Reported testing: Significant (p < 0.05) effect for fish oil (Arm 2) relative to oleic, palmitic, and linoleic acids (Arm 1) using paired univariate Student s t test. Quality: Jadad: 5 Concealment of allocation: NR Applicability: IIIB Sigmoidoscopic score: NA Funding source: NR Histological score (change at month 3): Arm 1= point estimate before cross-over not reported Arm 2 = point estimate before cross-over not reported Meta-anlysis: Not done; too few studies to pool. Reported testing: No significant difference between groups using paired univariate Student s t test. Induced remission: NA Relapse: NA Immunosupressive requirement: NA 251

264 Table C.2. Evidence table of clinical effect and association of omega-3 fatty acids with inflammatory bowel disease (continued). First Author, Year Study Characteristics Study Design Duration Eligibility Criteria Concurrent Disease Condition Medication Arm Belluzzi A, Sample size: Age (mean/range): NA / Race: NA % male: 50 # sites: NA Location: Italy Design: Duration: RCT 12 mo Inclusion: Remission of Crohn s disease/elevated serum markers of inflammation Exclusion: Steroid treatment/previous cytotoxic or immunosuppressive drug treatment/pregnancy/lactatin g/age between 18 and 75 years old/ Previous bowel resection of more than 1 m/ Previous sulphasalazine or mesalazine treatment Covariates: Previous surgery Interventions Dosage/Duration 1 Miglyol g/d x 12 mo 2 Fish oil, enteric coated 15 g/d x 12 mo 252

265 Table C.2. Evidence table of clinical effect and association of omega-3 fatty acids with inflammatory bowel disease (continued). First Author, Year Outcomes Results Quality Applicability Funding Source Belluzzi A, Clinical score: NA Quality: Jadad: 5 Sigmoidoscopic score: NA Concealment of allocation: NA Histological score: NA Induced remission: NA Applicability: IB Funding source: Industry Relapse (# of relapse at month 12) Arm 1 =27 Arm 2 =11 risk ratio=0.41 (0.24, 0.70) Reported testing: Article reports significant difference (p<0.001) between Arm 1 and Arm 2. Immunosupressive requirement: NA 253

266 Table C.2. Evidence table of clinical effect and association of omega-3 fatty acids with inflammatory bowel disease (continued). First Author, Year Study Characteristics Study Design Duration Eligibility Criteria Greenfield SM, Sample size: Age (mean/range): 54 / NA Race: NA % male: 70 # sites: NA Location: UK Design: Duration: RCT 9 mo Inclusion: Ulcerative colitis, Disease > 1 year/clinically stable/prednisone or prednisolone treatment < 10 mg/day Exclusion: NA Concurrent Disease Condition Medication Covariates: Sulphasalazine or mesalazine treatment (SASP)/Rectal steroids Arm Interventions Dosage/Duration 1 Olive oil Variable dose x 6 mo 2 Max EPA (fish oil) Variable dose x 6 mo 3 Super evening primrose oil (Borage and evening primrose oils) Variable dose x 6 mo 254

267 Table C.2. Evidence table of clinical effect and association of omega-3 fatty acids with inflammatory bowel disease (continued). First Author, Year Outcomes Results Quality Applicability Funding Source Greenfield SM, Clinical score: NA Sigmoidoscopic score (change at month 9): Arm 1= point estimate not reported Arm 2 = point estimate not reported Arm 3 = point estimate not reported Meta-anlysis: Not done; too few studies to pool. Reported testing: No significant difference between groups using Mann-Whitney U test. Quality: Jadad: 2 Concealment of allocation: NA Applicability: IB Funding source: NR Histological score(change at month 9): Arm 1= point estimate not reported Arm 2 = point estimate not reported Arm 3 = point estimate not reported Meta-anlysis: Not done; too few studies to pool. Reported testing: No significant difference between groups using Mann-Whitney U test Induced remission: NA Relapse(rate at month 9): Arm 1= point estimate not reported Arm 2 = point estimate not reported Arm 3 = point estimate not reported Meta-anlysis: This study was excluded from the meta-analysis of relapse because data was not reported separately by arm/group. The data was reported as number of patients in remission at entry. Reported testing: No significant difference between groups using Mann-Whitney U test Immunosuppressive requirement: NA

268 Table C.2. Evidence table of clinical effect and association of omega-3 fatty acids with inflammatory bowel disease (continued). First Author, Year Study Characteristics Study Design Duration Eligibility Criteria Hawthorne A, Sample size: Age (mean/range): 47 / Race: NA % male: 55 # sites: 2 Location: UK Design: RCT Duration: 14 mo Concurrent Disease Condition Medication Inclusion: Covariates: Sulphasalazine Biopsy-proven ulcerative colitis/ two or mesalazine treatment or more relapses in the previous 3 (SASP) years Exclusion: Prednisolone > 20 mg/likely to require surgery or deteriorating Arm Interventions Dosage/Duration 1 Olive oil 20 ml/d x 12 mo 2 Hi EPA (Fish oil) 20 ml/d x 12 mo 256

269 Table C.2. Evidence table of clinical effect and association of omega-3 fatty acids with inflammatory bowel disease (continued). First Author, Year Outcomes Results Quality Applicability Funding Source Hawthorne A, Clinical score: NA Sigmoidoscopic score: NA Quality: Jadad: 3 Concealment of allocation: Yes Histological score: NA Applicability: IIIB Induced remission (rate at month 12): Funding source: Industry and Arm 1= 63% Private, non-industry Arm 2 = 54% Meta-anlysis: Not done; too few studies to pool. Reported testing: No significant effect (p = 0.44) for fish oil (Arm 2) relative to olive oil (Arm 1) using log rank analysis and Kaplan Meier method. [ I think it s just Kaplan Meier] Relapse(rate at month 12): Arm 1= 48% Arm 2 = 42% Meta-anlysis: This study was excluded from the meta-analysis of relapse because the population was the same as another study that was included in the MA. 41 Reported testing: No significant effect (p = 0.54) for fish oil (Arm 2) relative to olive oil (Arm 1) using log rank analysis and Kaplan Meier method. I think it s just Kaplan Meier] Immunosuppressive requirement: (median prednisolone dose, mg at month 1, month 2) Arm 1: 6/5 Arm 2: 1/0 Meta-anlysis: Not done; too few studies to pool. Reported testing: Testing between arms not reported. 257

270 Table C.2. Evidence table of clinical effect and association of omega-3 fatty acids with inflammatory bowel disease (continued). First Author, Year Study Characteristics Study Design Duration Eligibility Criteria Concurrent Disease Condition Medication Hawthorne A 41 Sample size: 96 Age (mean/range): 47 / Race: NA % male: 55 # sites: 2 Location: UK Design: RCT Duration: 12 mo Inclusion: Biopsy-proven ulcerative colitis / two or more relapses in the previous 3 years Exclusion: Prednisolone > 20 mg/likely to require surgery or deteriorating Covariates: Sulphasalazine or mesalazine treatment (SASP) Arm Interventions Dosage/Duration 1 Olive oil 20 ml/d x 12 mo 2 Hi EPA (Fish oil) 20 ml/d x 12 mo 258

271 Table C.2. Evidence table of clinical effect and association of omega-3 fatty acids with inflammatory bowel disease (continued). First Author, Year Outcomes Results Quality Applicability Funding Source Hawthorne A 41 Clinical score: NA Sigmoidoscopic score: NA Histological score: NA Quality: Jadad: 3 Concealment of allocation: Yes Induced remission(rate at month 12): Arm 1: 70% Arm 2: 61% Meta-anlysis: Not done; too few studies to pool. Reported testing: Testing between arms not reported. Applicability: IIIB Funding source: Industry and Private, non-industry Relapse (# of relapse at month 12) Arm 1 =11 Arm 2 =15 risk ratio=1.32 (0.71, 2.46) Reported testing: Article reports no significant difference between Arm 1 and Arm 2 by survival analysis. Immunosuppressive requirement: NA 259

272 Table C.2. Evidence table of clinical effect and association of omega-3 fatty acids with inflammatory bowel disease (continued). First Author, Year Study Characteristics Study Design Duration Eligibility Criteria Loeschke K, Sample size: Age (mean/range): 40 / NA Race: NA Design: RCT Duration: 24 mo Inclus ion: Biopsy-proven ulcerative colitis/ At least 1 relapse in the last 2 years/gomes clinical score (IBD) below 8 Concurrent Disease Condition Medication Covariates: 5- ASA/Sulphasalazine or mesalazine treatment (SASP) Arm Interventions Dosage/Duration 1 Corn oil 6 ml/d x 24 mo 2 Fish oil 5 g/d x 24 mo % male: 52 # sites: 2 Location: Germany Exclusion: Steroid treatment/pregnancy/cytotoxic or immunosuppressive drug treatment/questionable adherence 260

273 Table C.2. Evidence table of clinical effect and association of omega-3 fatty acids with inflammatory bowel disease (continued). First Author, Year Outcomes Results Quality Applicability Funding Source Loeschke K, Clinical score(change from graph data at month 24): Arm 1: +0.7 Arm 2: Meta-anlysis: Not done; too few studies to pool. Reported testing: No significant difference between groups using two-way analysis of variance. Quality: Jadad: 5 Concealment of allocation: NA Applicability: IB Sigmoidoscopic score: NA Funding source: Industry Histological score (at month 24): Arm 1= point estimate not reported Arm 2= point estimate not reported Meta-anlysis: Not done; too few studies to pool. Reported testing: No significant difference between groups using Mann-Whiney U test. Induced remission: NA Relapse (# of relapse at month 24) Arm 1 =18 Arm 2 =18 risk ratio=1.06 (0.69, 1.64) Reported testing: Article reports no significant difference between Arm 1 and Arm 2 by chi-square test. Immunosuppressive requirement: NA 261

274 Table C.2. Evidence table of clinical effect and association of omega-3 fatty acids with inflammatory bowel disease (continued). First Author, Year Study Characteristics Study Design Duration Eligibility Criteria Lorenz R, Sample size: Age (mean/range): 37 / Race: NA % male: 41 # sites: 1 Design: RXT Duration: 7 mo X-over: month 3 Run-in: None Wash-out: 1 mo Inclusion: Biopsy-proven Crohn s disease or ulcerative colitis Exclusion: Pregnancy/Pending surgery, abscesses or severe bleeding/questionable adherence/prednisone>8 mg/day/inactive disease Concurrent Disease Condition Medication Covariates: Sulphasalazine or mesalazine treatment (SASP)/Flagyl Arm Interventions Dosage/Duration 1 Olive oil 11 ml/d x 3 mo 2 Max EPA (fish oil) 11 ml/d x 3 mo Location: Germany Lorenz-Meyer Sample size: 204 H, Age (mean/range): 31 / Race: NA % male: 33 # sites: 23 Location: Germany Design: RCT Duration: 12 mo Inclusion: Biopsy-proven Crohn s disease/active disease/steroid treatment Exclusion: Questionable adherence/pregnancy/cytotoxic or immunosuppressive drug treatment/nsaid treatment/sulphasalazine or mesalazine treatment/total parenteral nutrition (TPN)/Short bowel syndrome/steatorrhea Covariates: Fistula 1 Corn oil 6 g/d x 12 mo 2 Low-carbohydate diet Dosage NA x 12 mo 3 Fish oil 6 g/d x 12 mo 262

275 Table C.2. Evidence table of clinical effect and association of omega-3 fatty acids with inflammatory bowel disease (continued). First Author, Year Outcomes Results Quality Applicability Funding Source Lorenz R, Clinical score(change from graph data at month 3): Arm 1= -12 Crohn s Disease Activity Index -2 Ulcerative Colitis Activity Index Arm 2 = -3 Crohn s Disease Activity Index -2 Ulcerative Colitis Activity Index Meta-anlysis: Not done; too few studies to pool. Reported testing: No significant difference between groups using Sigmoidoscopic score (change at month 3): Arm 1= point estimate before cross-over not reported Arm 2 = point estimate before cross-over not reported Meta-anlysis: Not done; too few studies to pool. Reported testing: Significant (p < 0.05) effect for fish oil (Arm 2) relative to olive oil (Arm 1) using Quality: Jadad: 5 Concealment of allocation: Yes Applicability: IB Funding source: Unclear Histological score: NA Induced remission: NA Relapse: NA Immunosuppressive requirement: NA Lorenz-Meyer H, Clinical score: NA Sigmoidoscopic score: NA Histological score: NA Induced remission: NA Relapse (# of relapse at month 12) Arm 1 =36 Arm 3 =40 risk ratio=1.03 (0.77, 1.39) Reported testing: Article did not report statistical results comparing Arm 1 and Arm 3. Quality: Jadad: 3 Concealment of allocation: NA Applicability: IB Funding source: NA Immunosuppressive requirement: NA 263

276 Table C.2. Evidence table of clinical effect and association of omega-3 fatty acids with inflammatory bowel disease (continued). First Author, Year Study Characteristics Study Design Duration Eligibility Criteria Mantzaris GJ, Sample size: Age (mean/range): 36 / Race: NA % male: 48 # sites: NA Location: Greece Design: Duration: RCT 12 mo Inclusion: Remission of biopsy-proven ulcerative colitis/mesalazine treatment Exclusion: NA Concurrent Disease Condition Medication Covariates: Sulphasalazine or mesalazine treatment (SASP) Arm Interventions Dosage/Duration 1 Olive oil 20 ml/d x 12 mo 2 Max EPA (fish oil) 20 ml/d x 12 mo 264

277 Table C.2. Evidence table of clinical effect and association of omega-3 fatty acids with inflammatory bowel disease (continued). First Author, Year Outcomes Results Quality Applicability Funding Source Mantzaris GJ, Clinical score: NA Sigmoidoscopic score: NA Histological score: NA Induced remission: NA Relapse (# of relapse at month 12) Arm 1 =5 Arm 2 =6 risk ratio=0.98 (0.36, 2.70) Reported testing: Article reports no significant difference (p>0.1) between Arm 1 and Arm 2 by chisquare test. Immunosuppressive requirement: NA Quality: Jadad: 2 Concealment of allocation: NA Applicability: IB Comments: This study is included in the meta-analysis of relapse. Funding source: NA 265

278 Table C.2. Evidence table of clinical effect and association of omega-3 fatty acids with inflammatory bowel disease (continued). First Author, Year Study Characteristics Study Design Duration Eligibility Criteria Middleton SJ, Sample size: Age (mean/range): 42 / Race: NA % male: 50 # sites: 1 Location: UK Design: Duration: RCT 12 mo Inclusion: Age between 18 and 70 years old/biopsy-proven ulcerative colitis in remission Exclusion: Serious liver disease/malignant disease/pregnancy/lactating/ Antiplatelet or anticoagulating treatment/epilepsy/lithium or phenothiazine/serious renal disease Concurrent Disease Condition Medication Covariates: Smoking/Sulphasalazine or mesalazine treatment (SASP)/5-ASA Arm Interventions Dosage/Duration 1 Sunflower oil 6 cap/d x 12 mo 2 GLA+ EPA+DHA 6 cap/d x 12 mo 266

279 Table C.2. Evidence table of clinical effect and association of omega-3 fatty acids with inflammatory bowel disease (continued). First Author, Year Outcomes Results Quality Applicability Funding Source Middleton SJ, Clinical score: NA Sigmoidoscopic score (at month 12): Arm 1= point estimate not reported Arm 2 = point estimate not reported Meta-anlysis: Not done; too few studies to pool. Reported testing: No significant difference between groups using proportional Cox hazard regression. Histological score: NA Induced remission: NA Relapse (rate at month 12, extrapolated from graph): Arm 1= 38% Arm 2 = 55% Meta-anlysis: Not included in MA; point estimates not reported. Reported testing: No significant difference between groups using proportional Cox hazard regression. Immunosuppressive requirement: NA Quality: Jadad: 3 Concealment of allocation: NR Applicability: IB Funding source: NR 267

280 Table C.2. Evidence table of clinical effect and association of omega-3 fatty acids with inflammatory bowel disease (continued). First Author, Year Study Characteristics Study Design Duration Eligibility Criteria Stenson WF, Sample size: Age (mean/range): 42 / Race: NA % male: 56 # sites: 4 Location: US Design: RXT Duration: 9 mo X-over: month 4 Run-in: None Wash-out: 1 mo Inclusion: Ulcerative colitis Active disease Exclusion: NA Concurrent Disease Condition Medication Covariates: Rectal steroids/sulphasalazine or mesalazine treatment (SASP) Arm Interventions Dosage/Duration 1 Vegetable oil 18 cap/d x 4 mo 2 Max EPA (fish oil) 18 cap/d x 4 mo 268

281 Table C.2. Evidence table of clinical effect and association of omega-3 fatty acids with inflammatory bowel disease (continued). First Author, Year Outcomes Results Quality Applicability Funding Source Stenson WF, Clinical score (change at month 4): Arm 1= point estimate before cross-over not reported Arm 2 = point estimate before cross-over not reported Meta-anlysis: Not done; too few studies to pool. Reported testing: Significant (P < 0.14) effect for fish oil (Arm 2) relative to vegetable oil (Arm 1) using ranksign test. Sigmoidoscopic score (change at month 4): Arm 1= point estimate before cross-over not reported Arm 2 = point estimate before cross-over not reported Meta-anlysis: Not done; too few studies to pool. Reported testing: Testing between arms not reported. Histological score(change at month 4): Arm 1= point estimate before cross-over not reported Arm 2 = point estimate before cross-over not reported Meta-anlysis: Not done; too few studies to pool. Reported testing: Testing between arms not reported. Induced remission: NA Relapse: NA Immunosuppressive requirement (mean prednisolone dose 8 in mg at month 4) Arm 1: 12.9 Arm 2: 6.1 Meta-anlysis: Not done; too few studies to pool. Reported testing: Testing between arms not reported. Quality: Jadad: 2 Concealment of allocation: NA Applicability: NA Funding source: Government and Private, non-industry 269

282 Table C.2. Evidence table of clinical effect and association of omega-3 fatty acids with inflammatory bowel disease (continued). First Author Year Study Characteristics Study Design Duration Eligibility Criteria Varghese TJ, Sample size: Age (mean/range): NA / NA Race: NA % male: 99 # sites: NA Location: UK Design: RCT Duration: 6 mo Inclusion: Ulcerative colitis and extensive disease Exclusion: Cytotoxic or immunosuppressive drug treatment Concurrent Disease Condition Medication Covariates: NA Arm Interventions Dosage/Duration 1 Sunflower oil Dosage NA x 12 mo 2 Omega-3 EFAs 6 mg/d x 6 mo 270

283 Table C.2. Evidence table of clinical effect and association of omega-3 fatty acids with inflammatory bowel disease (continued). First Author, Year Outcomes Results Quality Applicability Funding Source Varghese TJ, Clinical score (change at month 6): Arm 1= point estimate not reported Arm 2 = point estimate not reported Meta-anlysis: Not done; too few studies to pool. Reported testing: Significant (p = 0.001) effect for Omega-3 EFAs (Arm 2) relative to sunflower oil (Arm 1). Quality: Jadad: 2 Concealment of allocation: NA Applicability: NA Sigmoidoscopic score (change at month 6): Arm 1= point estimate not reported Arm 2 = point estimate not reported Meta-anlysis: Not done; too few studies to pool. Reported testing: Significant (p = 0.054) effect for Omega-3 EFAs (Arm 2) relative to sunflower oil (Arm 1). Funding source: NA Histological score: NA Induced remission: NA Relapse: NA Immunosuppressive requirement: NA 271

284 Table C.3. Evidence table of clinical effect of omega-3 fatty acids in rheumatoid arthritis First Author, Year Study Characteristics Study Design Duration Eligibility Criteria Adam O, Sample size: NA Age (mean/range): 57 / NA Race: NA % male: 7 # sites: NA Location: Germany Design: RXT Duration: 8 mo X-over: month 5 Run-in: None Wash-out: 2 mo Inclusion: >= 6 tender joints/>= 3 swollen joints/ AND one or both : morning stiffness >= 30 min/ elevated ESR or CRP Exclusion: Prednisone > 10 mg/d/gi disorders/alcohol use/metabolic disease/known allergies Concurrent Disease Condition Medication Covariates: Diet Arm Interventions Dosage/Duration 1 Western diet Corn oil capsules 1g/10 kg body weight/day X 3 mo 2 Placebo/control Modified lacto- vegetarian diet Corn oil capsules 1g/10 kg body weight/day X 3 mo 3 Western diet Menhaden oil 1g/10 kg body weight/day X 3 mo 4 Modified lacto-vegetarian diet Menhaden oil 1g/10 kg body weight/day X 3 mo 272

285 Table C.3. Evidence table of clinical effect of omega-3 fatty acids in rheumatoid arthritis (continued). First Author, Outcomes Year Results Adam O, Pain (cm on VAS at month 3) Arms 1, 2, 3, 4 = point estimate not reported Meta-analysis: Not included, point estimates not reported. Reported testing: Testing between placebo (arms 1 and 2) and fish oil (arms 3 and 4) not reported. Swollen joints (number at month 3): Arms 1, 2, 3, 4 = point estimate not reported Meta-analysis: Not included, point estimates not reported. Reported testing: Testing between placebo (arms 1 and 2) and fish oil (arms 3 and 4) not reported. Quality Applicability) Funding Source Quality: Jadad: 3 Concealment of allocation: NR Applicability: IIB Funding source: Government Acute phase reactant: NA Patient global assessment (at month 3): Arms 1, 2, 3, 4 = point estimate not reported Meta-analysis: Not included, point estimates not reported. Reported testing: Testing between placebo (arms 1 and 2) and fish oil (arms 3 and 4) not reported. Radiographic damage: NA NSAID consumption (at month 3): Arms 1, 2, 3, 4 = point estimate not reported Meta-analysis: Not performed, too few studies to pool. Reported testing: Testing between placebo (arms 1 and 2) and fish oil (arms 3 and 4) not reported. Steroid consumption (at month 3): Arms 1, 2, 3, 4 = point estimate not reported Meta-analysis: : Not performed, too few studies to pool. Reported testing: Testing between placebo (arms 1 and 2) and fish oil (arms 3 and 4) not reported. DMARD consumption: NA 273

286 Table C.3. Evidence table of clinical effect of omega-3 fatty acids in rheumatoid arthritis (continued). First Author, Year Study Characteristics Study Design Duration Eligibility Criteria Concurrent Disease Condition Medication Alpigiani M, Sample size: Age (mean/range): 14 / NA Race: NA Design: Duration: 6 mo Inclusion: Juvenile chronic arthritis/age 4-13 Exclusion: NA Covariates: NA Arm 1 Diet Interventions Dosage/Duration 2 Cod-liver oil (Eskisol) 5 g/d x 6 mo % male: 44 # sites: 1 Location: Italy 274

287 Table C.3. Evidence table of clinical effect of omega-3 fatty acids in rheumatoid arthritis (continued). First Author, Outcomes Year Results Alpigiani M, Pain: NA Swollen joints: NA Acute phase reactant: (change at month 6, CRP, mg%): Arm 1: Arm 2: Meta-analysis: Not included; point estimates not reported. Reported testing: Significant (p=.009) difference between arms by ANOVA. Quality: Jadad: 1 Concealment of allocation: NR Applicability: IIB Funding source: NA Patient global assessment: NA Radiographic damage: NA NSAID consumption: NA Steroid consumption: NA DMARD consumption: NA 275

288 Table C.3. Evidence table of clinical effect of omega-3 fatty acids in rheumatoid arthritis (continued). First Author, Year Study Characteristics Study Design Duration Eligibility Criteria Concurrent Disease Condition Medication Belch JF, Sample size: 49 Age (mean/range): 49 / Race: NA % male: 12 # sites: NA Design: RCT Duration: 15 mo Inclusion: NSAIDs use/no DMARDs Exclusion: NA Covariates: Evening primrose oil Arm Interventions Dosage/Duration 1 Placebo: Liquid paraffin capsules 12/d x 12 months 2 Fish oil (240 mg EPA) plus evening primrose oil (540 mg GLA) daily x 12 mo 3 Evening primrose oil (540 mg GLA) daily x 12 mo Location: UK 276

289 Table C.3. Evidence table of clinical effect of omega-3 fatty acids in rheumatoid arthritis (continued). First Author, Outcomes Year Results Belch JF, Pain (cm on VAS at month 12) Arms 1, 2, 3 = point estimate not reported Meta-analysis: Not included, point estimates not reported. Reported testing: No difference between groups using Mann-Whitney U test. Swollen joints (number at month 3): Arms 1, 2, 3 = point estimate not reported Meta-analysis: Not included, point estimates not reported. Reported testing: No difference between groups using Mann-Whitney U test. Acute phase reactant: (CRP and ESR at month 12) Arms 1, 2, 3 = point estimate not reported Meta-analysis: Not included, point estimates not reported. Reported testing: No difference in CRP or ESR between groups using Mann-Whitney U test. Quality Applicability Funding Source Quality: Jadad: 4 Concealment of allocation: NR Applicability: IIB Comments: Meta-analysis not performed because of insufficient statistics ; study only reported data in graph. Funding source: Private, nonindustry Patient global assessment: NA Radiographic damage: NA NSAID consumption (at month 15): Arm 1: Reduced in 33% of subjects Arm 2: Reduced in 80% of subjects Arm 3: Reduced in 73% of subjects Meta-analysis: Not performed, too few studies to pool. Reported testing: Testing between groups not reported. Steroid consumption: NA DMARD consumption: NA 277

290 Table C.3. Evidence table of clinical effect of omega-3 fatty acids in rheumatoid arthritis (continued). First Author, Year Study Characteristics Study Design Duration Eligibility Criteria Concurrent Disease Condition Medication Arm Interventions Dosage/Duration Cleland LG, Sample size: 60 Age (mean/range): 51 / Design: RCT Duration: 3 mo Inclusion: NA Exclusion: NA Covariates: NSAIDs/DMARDs 1 Olive oil 18 g/d x 3 mo Race: NA % male: 30 2 Max EPA (fish oil) 18 g/d x 3 mo # sites: NA Location: Australia 278

291 Table C.3. Evidence table of clinical effect of omega-3 fatty acids in rheumatoid arthritis (continued). First Author, Outcomes Year Results Cleland LG, Pain (Analogue pain scale at month 3) Arm 1 =7.1 Arm 2 =7 effect size=-0.02(-0.60, 0.56) Reported testing: Article did not report statistical results comparing Arm 1 and Arm 2. Swollen joints (# of swollen joint at month 3) Arm 1 =3.5 Arm 2 =3.6 effect size=0.04(-0.54, 0.62) Reported testing: Article did not report statistical results comparing Arm 1 and Arm 2. Quality Applicability Funding Source Quality: Jadad: 3 Concealment of allocation: NR Applicability: IB Funding source: Government; Private, non-industry; Hospital Acute phase reactant: (ESR at month 12) Arms 1, 2 = point estimate not reported Meta-analysis: Not included, point estimates not reported. Reported testing: No significant change within group by Student s t test; testing between groups not reported. Patient global assessment: (at month 12) Arms 1, 2 = point estimate not reported Meta-analysis: Not included, point estimates not reported. Reported testing: No significant change within group; testing between groups not reported. Radiographic damage: NA NSAID consumption NA Steroid consumption: NA DMARD consumption: NA 279

292 Table C.3. Evidence table of clinical effect of omega-3 fatty acids in rheumatoid arthritis (continued). First Author, Year Study Characteristics Study Design Duration Eligibility Criteria Concurrent Disease Condition Medication Geusens P, Sample size: 90 Age (mean/range): 57 / NA Race: NA % male: 22 Design: RCT Duration: 12 mo Inclusion: Active disease Exclusion: NA Covariates: NSAIDs/DMARDs Arm Interventions Dosage/Duration 1 Olive oil capsules 6 g/d x 12 mo 2 Fish oil 3 g x 12 mo plus olive oil 3 g/d x 12 mo 3 Fish oil 6 g/d x 12 mo # sites: NA Location: Belgium 280

293 Table C.3. Evidence table of clinical effect of omega-3 fatty acids in rheumatoid arthritis (continued). First Author, Outcomes Year Results Quality Applicability) Funding Source Geusens P, Pain (0-4 scale at month 3) Arm 1 =1.97 Arm 2 and Arm 3 (combined) =1.89 effect size=-0.04(-0.57, 0.50) Reported testing: Article reports no significant differences (p>0.05) of the changes between Arm 2 or Arm 3 and Arm 1. Swollen joint:s NA Acute phase reactant: NA Radiographic damage:na NSAID consumption: consumption of NSAIDs and DMARDs combined reported, see below. Steroid consumption: NA DMARD consumption: consumption of NSAIDs and DMARDs combined reported, see below. Patient global assessment (0-10cm visual analog scale at month 3) Arm 1 =5.68 Arm 2 and Arm 3 (combined) =4.53 effect size=-1.38(-1.97, -0.79) Reported testing: Article reports significant differences (p<0.01) of the changes between Arm 3 and Arm1 by Mann-Whitney test. NSAID and/or DMARD consumption: (% with dose reduction at month 12) Arm 1 = 15 Arm 2 = 29 Arm 3 = 47 Meta-analysis: Not done, too few studies to pool. Reported testing: Significant (p<.05) difference between arms 3 (high dose fish oil) and arm 1 (placebo) using chi-square test. Quality: Jadad: 3 Concealment of allocation: NR Applicability: IB Funding source: ND 281

294 Table C.3. Evidence table of clinical effect of omega-3 fatty acids in rheumatoid arthritis (continued). First Author, Year Study Characteristics Study Design Duration Eligibility Criteria Concurrent Disease Condition Medication Arm Interventions Dosage/Duration Hansen G, Sample size: 109 Age (mean/range): 57 / NA Race: NA % male: 26 # sites: NA Location: Denmark Design: RCT Duration: 6.0 mo Inclusion: Increased morning stiffness/increased sed rate/>= 3 swollen joints Exclusion: Underweight/Severe disorders Covariates: NSAIDs 1 Normal diet 2 Fish 114 g for 6 mo 282

295 Table C.3. Evidence table of clinical effect of omega-3 fatty acids in rheumatoid arthritis (continued). First Author, Outcomes Year Results Hansen G, Pain: (change on VAS at month 6) Arm 1 = 0.2 Arm 2 = -0.2 Meta-analysis: Not included, point estimates not reported. Reported testing: Significant (p=0.01) difference between arms using Wilcoxons unpaired rank test. Swollen joints: (change on 1-3 scale at month 6) Arm 1 = -1 Arm 2 = -3 Meta-analysis: Not included, point estimates not reported. Reported testing: Significant (p=0.01) difference between arms using Wilcoxons unpaired rank test. Quality Applicability) Funding Source Quality: Jadad: 1 Concealment of allocation: NR Applicability: IB Funding source: ND Acute phase reactant: (change, ESR, mm/hr at month 6) Arm 1 = 0 Arm 2 = 1 Meta-analysis: Not included, point estimates not reported. Reported testing: No significant difference between arms using Wilcoxons unpaired rank test. Patient global assessment: NA Radiographic damage: (Change, Larsen score at month 6) Arm 1 = 4 Arm 2 = 3 Meta-analysis: Not included, point estimates not reported. Reported testing: No significant difference between arms using Wilcoxons unpaired rank test. NSAID consumption: Arm 1 = point estimate not reported Arm 2 = point estimate not reported Meta-analysis: Not performed, too few studies to pool. Reported testing: Testing between groups not reported. Steroid consumption: NA DMARD consumption: NA 283

296 Table C.3. Evidence table of clinical effect of omega-3 fatty acids in rheumatoid arthritis (continued). First Author, Year Study Characteristics Study Design Duration Eligibility Criteria Concurrent Disease Condition Medication Kjeldsen-Kragh J, Sample size: Age (mean/range): 57 / Race: NA % male: 24 # sites: 7 Location: Russia Design: RCT Duration: 4.0 mo Inclusion: Covariates: >= 6 tender joints/>= 3 swollen Naproxen joints/increased sed rate/increased morning stiffness/prednisone or prednisolone = 10 mg/functional class/stable medication Exclusion: NA Arm Interventions Dosage/Duration 1 Corn oil 7g/d X 16 weeks Naproxen 750 mg/d x 10 weeks then reduction to 0 mg/d by week 13 continued through week K-85 (fish oil) 750 mg for 16 wk Naproxen 750 mg/d X 16 weeks 3 K-85 (fish oil) 750 mg for 16 wk Naproxen 750 mg/d x 10 weeks then reduction to 0mg/d by week 13 continued through week

297 Table C.3. Evidence table of clinical effect of omega-3 fatty acids in rheumatoid arthritis (continued). First Author, Outcomes Year Results Kjeldsen-Kragh J, Pain: (VAS at week 16) Arms 1, 2, 3: point estimates not reported. Meta-analysis: Not included, point estimates not reported. Reported testing: Testing between groups not reported. Swollen joints: (number at month 16) Arms 1, 2, 3: point estimates not reported. Meta-analysis: Not included, point estimates not reported. Reported testing: Testing between groups not reported. Quality Applicability Funding Source Quality: Jadad: 3 Concealment of allocation: NR Applicability: IB Funding source: Private, nonindustry Acute phase reactant: NA Patient global assessment: (at week 16) Arms 1, 2, 3: point estimates not reported. Meta-analysis: Not included, point estimates not reported. Reported testing: Testing between groups not reported. Radiographic damage: NA NSAID consumption: NA Steroid consumption: NA DMARD consumption: NA 285

298 Table C.3. Evidence table of clinical effect of omega-3 fatty acids in rheumatoid arthritis (continued). First Author, Year Study Characteristics Study Design Duration Eligibility Criteria Concurrent Disease Condition Medication Kremer J, Sample size: 64 Age (mean/range): 58 / Race: NA % male: 33 # sites: 1 Location: US Design: RCT Duration: 9 mo Inclusion: Covariates: >= 6 tender joints/increased sed NSAIDs/DMARDs rate/increased morning stiffness/stable medication/>= 3 swollen joints Exclusion: NA 1 Arm Interventions Dosage/Duration Olive oil capsules 9/d X 24 weeks 2 Fish oil capsules X 24 weeks (27 mg/kg/d EPA, 18 mg/kg/d DHA) 3 Fish oilcapsules X 24 weeks (54 mg/kg/d EPA, 36 mg/kg/d DHA) 286

299 Table C.3. Evidence table of clinical effect of omega-3 fatty acids in rheumatoid arthritis (continued). First Author, Outcomes Year Results Kremer J, Pain (0-4 five point scale at week 12) Arm 1 =1.60 Arm 2 and Arm3 (combined) =1.51 effect size=-0.04(-0.69, 0.61) Reported testing: Article did not report statistical results comparing Arm 1 and Arm 2 and Arm 3. Swollen joints (# of swollen joint at week 12) Arm 1 =13.50 Arm 2 and Arm3 (combined) =10.96 effect size=-0.63(-1.30, 0.03) Reported testing: Article did not report statistical results comparing Arm 1 and Arm 2 and Arm 3. Quality Applicability Funding Source Quality: Jadad: 2 Concealment of allocation: NR Applicability: IB Funding source: NA Acute phase reactant: (ESR at week 24 and at week 36) Arms 1,2,3 = point estimates not reported. Meta-analysis: Not included, point estimates not reported. Reported testing: No significant difference in any arm using Student s t-test; testing between groups not reported. Patient global assessment (0-4 five point scale at week 12) Arm 1 =1.8 Arm 2 and Arm3 (combined) =1.69 effect size=-0.13(-0.78, 0.52) Reported testing: Article did not report statistical results comparing Arm 1 and Arm 2 and Arm 3. Radiographic damage: NA NSAID consumption: NA Steroid consumption: NA DMARD consumption: NA 287

300 Table C.3. Evidence table of clinical effect of omega-3 fatty acids in rheumatoid arthritis (continued). First Author, Year Study Characteristics Study Design Duration Eligibility Criteria Concurrent Disease Condition Medication Kremer J, Sample size: 66 Age (mean/range): 58 / NA Design: RCT Duration: 6.5 mo Inclusion: >= 6 tender joints/>= 3 swollen joints/increased morning stiffness/increased sed rate Covariates: DMARDs/NSAIDs Arm Interventions Dosage/Duration 1 Corn oil, 9 capsules/d X 26 or 30 wk. Diclofenac, 75 mg BID X first 18 or 22 wk Race: NA % male: 45 # sites: 3 Location: US Exclusion: NA 2 Menhaden oil (130 mg/kg/d of omega-3) X 26 or 30 wk, then corn oil until week 48. Diclofenac, 75 mg BID X first 18 or 22 wk 288

301 Table C.3. Evidence table of clinical effect of omega-3 fatty acids in rheumatoid arthritis (continued). First Author, Outcomes Year Results Kremer J, Pain: (0-4 scale, mean change at week 18 or 22) Arm 1= point estimate not reported Arm 2 = point estimate not reported Meta-analysis: Not included because point estimates not reported. Reported testing: Not reported for this outcome. Tender joints: (number, change at week 18 or 22) Arm 1= point estimate not reported Arm 2 = -5.3 Meta-analysis: Not included because point estimate not reported for control group. Reported testing: Testing between groups not reported. Quality Applicability Funding Source Quality: Jadad: 2 Concealment of allocation: NR Applicability: IB Funding source: NR Swollen joints: (number at week 18 or 22) Arm 1= point estimate not reported Arm 2 = point estimate not reported Meta-analysis: Not included because point estimates not reported. Reported testing: Not reported for this outcome. Acute phase reactant: NA Patient global assessment: (mean change at week 18 or 22) Arm 1= point estimate not reported Arm 2 = Meta-analys is: Not included because point estimate not reported for control group. Reported testing: Testing between groups not reported. Radiographic damage: NA NSAID consumption: Defined in study protocol Steroid consumption: NA DMARD consumption: NA 289

302 Table C.3. Evidence table of clinical effect of omega-3 fatty acids in rheumatoid arthritis (continued). First Author, Year Study Characteristics Study Design Duration Eligibility Criteria Concurrent Disease Condition Medication Kremer J, Sample size: 52 Age (mean/range): 56 / NA Race: NA % male: 32 # sites: NA Location: US Design: RCT Duration: 3 mo Inclusion: Increased sed rate/>= 6 tender joints/>= 3 swollen joints/increased morning stiffness Exclusion: Reliable adherence Covariates: NSAIDs/DMARDs Arm Interventions Dosage/Duration 1 Parafin placebo capsules 10/day X 12 weeks Diet with polyunsaturated fat: saturated fat ratio=1:4. 2 Max EPA (fish oil) capsules 10/d X 12 wk Diet with polyunsaturated fat: saturated fat ratio=1.4:1. 290

303 Table C.3. Evidence table of clinical effect of omega-3 fatty acids in rheumatoid arthritis (continued). First Author, Outcomes Year Results Kremer J, Pain (1-5 five point scale at week 12) Arm 1 =2.8 Arm 2 =2.5 effect size=-0.13(-0.78, 0.51) Reported testing: Article did not report statistical results comparing Arm 1 and Arm 2. Swollen joints (# of swollen joint at week 12) Arm 1 =13.5 Arm 2 =13.4 effect size=-0.02(-0.66, 0.63) Reported testing: Article did not report statistical results comparing Arm 1 and Arm 2. Quality Applicability Funding Source Quality: Jadad: 4 Concealment of allocation: NR Applicability: IB Funding source: NA Acute phase reactant Arm 1 =34.9 Arm 2 =24.2 effect size=-0.44(-1.10, 0.21) Reported testing: Article did not report statistical results comparing Arm 1 and Arm 2. Patient global assessment (1-5 five point scale at week 12) Arm 1 =2.9 Arm 2 =2.7 effect size=-0.24(-0.89, 0.41) Reported testing: Article did not report statistical results comparing Arm 1 and Arm 2. Radiographic damage: NA NSAID consumption: NA Steroid consumption: NA DMARD consumption: NA 291

304 Table C.3. Evidence table of clinical effect of omega-3 fatty acids in rheumatoid arthritis (continued). First Author, Year Study Characteristics Study Design Duration Eligibility Criteria Concurrent Disease Condition Medication Lau CS, Sample size: 45 Age (mean/range): NA / Race: NA Design: RCT Duration: 6 mo Inclusion: NSAIDs use/clinically stable/no DMARDs Exclusion: NA Covariates: NSAIDs Arm Interventions Dosage/Duration 1 Air-filled placebo capsules 10/day X 6 mo 2 Max EPA (fish oil) 10/day X 6 mo % male: 29 # sites: 1 Location: UK 292

305 Table C.3. Evidence table of clinical effect of omega-3 fatty acids in rheumatoid arthritis (continued). First Author, Outcomes Year Results Lau CS, Pain: (at month 6) Arm 1= point estimate not reported Arm 2 = point estimate not reported Meta-analysis: Not included; point estimates not reported. Reported testing: No statistically significant change within or between groups by ANOVA. Swollen joints: (at month 6) Arm 1= point estimate not reported Arm 2 = point estimate not reported Meta-analysis: Not included; point estimates not reported. Reported testing: No statistically significant change within or between groups by ANOVA. Quality Applicability) Funding Source Quality: Jadad: 2 Concealment of allocation: NR Applicability: IB Funding source: ND Acute phase reactant: (ESR at month 6) Arm 1= point estimate not reported Arm 2 = point estimate not reported Meta-analysis: Not included; point estimates not reported. Reported testing: No statistically significant change within or between groups by ANOVA. Patient global assessment: NA Radiographic damage: NA NSAID consumption: NA Steroid consumption: NA DMARD consumption: NA 293

306 Table C.3. Evidence table of clinical effect of omega-3 fatty acids in rheumatoid arthritis (continued). First Author, Year Study Characteristics Study Design Duration Eligibility Criteria Concurrent Disease Condition Medication Arm Interventions Dosage/Duration Lau CS, Sample size: 64 Age (mean/range): 51 / Race: NA Design: RCT Duration: 15 mo Inclusion: NSAIDs use/clinically stable/no DMARDs Exclusion: NA Covariates: NSAIDs 1 Air-filled placebo capsules 10/day X 12 mo 2 Max EPA (fish oil) capsules 10/day X 12 mo % male: 30 # sites: 1 Location: Scotland 294

307 Table C.3. Evidence table of clinical effect of omega-3 fatty acids in rheumatoid arthritis (continued). First Author, Outcomes Year Results Lau CS, Pain: (VAS at month 6) Arm 1= point estimate not reported Arm 2 = point estimate not reported Meta-analysis: Not included; point estimates not reported. Reported testing: No statistically significant change between groups by Wilcoxon rank sum test. Swollen joints: NA Quality Applicability) Funding Source Quality: Jadad: 3 Concealment of allocation: NR Applicability: IIB Funding source: Industry Acute phase reactant: (ESR at month 6) Arm 1= point estimate not reported Arm 2 = point estimate not reported Meta-analysis: Not included; point estimates not reported. Reported testing: No statistically significant change within or between groups by ANOVA. Patient global assessment: NA Radiographic damage: NA NSAID consumption: (% requiring at month 15) Arm 1 = 86 Arm 2 = 45 Meta-analysis: Not performed, too few studies to pool. Reported testing: No statistically significant change within or between groups by ANOVA. Steroid consumption: NA DMARD consumption: NA 295

308 Table C.3. Evidence table of clinical effect of omega-3 fatty acids in rheumatoid arthritis (continued). First Author, Year Study Characteristics Study Design Duration Eligibility Criteria Concurrent Disease Condition Medication Arm Interventions Dosage/Duration Magaro M, Sample size: 20 Age (mean/range): NA / Race: NA % male: NA # sites: NA Location: Italy Design: RCT Duration: 1.5 mo Inclusion: Covariates: NSAIDs Increased sed rate/>= 6 tender joints/>= 3 swollen joints/increased morning stiffness/nsaids use/no DMARDs Exclusion: Diabetes/Obesity 1 Usual diet 2 Max EPA (fish oil) 9 g/d x 45 days Usual diet 296

309 Table C.3. Evidence table of clinical effect of omega-3 fatty acids in rheumatoid arthritis (continued). First Author, Outcomes Year Results Magaro M, Patient assess pain (cm at day 45) Arm 1 =4.20 Arm 2 =4.80 effect size=0.41 (-0.48, 1.29) Reported testing: Article did not report statistical results comparing Arm 1 and Arm 2. Swollen joints: NA Quality Applicability Funding Source Quality: Jadad: 1 Concealment of allocation: NR Applicability: IIB Funding source: ND Acute phase reactant (mm/1 st hour at day 45) Arm 1 =66.00 Arm 2 =59.50 effect size=-0.16 (-1.04, 0.72) Reported testing: Article did not report statistical results comparing Arm 1 and Arm 2. Patient global assessment: NA Radiographic damage: NA NSAID consumption: NA Steroid consumption: NA DMARD consumption: NA 297

310 Table C.3. Evidence table of clinical effect of omega-3 fatty acids in rheumatoid arthritis (continued). First Author, Year Study Characteristics Study Design Duration Eligibility Criteria Concurrent Disease Condition Medication Arm Interventions Dosage/Duration Magalish T, Sample size: 112 Age (mean/range): NA / Race: NA % male: 26 # sites: 2 Location: Russia Design: CCT Duration: 10 d Inclusion: Age Exclusion: NA Covariates: Duration of diabetes 1 Phonopheresis with hydrocortisone cream q/d X 10 d 2 Phonopheresis with omega-3 fatty acids q/d 10 d 298

311 Table C.3. Evidence table of clinical effect of omega-3 fatty acids in rheumatoid arthritis (continued). First Author, Outcomes Year Results Magalish T, Pain: (unspecified measure at day 10) Arm 1 = 0.7 Arm 2 = 0.6 Meta-analysis: Not included; measure not defined. Reported testing: Testing between groups not reported. Swollen joints (# of swollen joint at month 0.3) Arm 1 =0.7 Arm 2 =0.6 effect size=-0.02(-0.66, 0.63) Reported testing: Unable to translate. Quality Applicability Funding Source Quality: Jadad: 0 Concealment of allocation: NR Applicability: IIB Funding source: NR Acute phase reactant: NA Patient global assessment: NA Radiographic damage: NA NSAID consumption: NA Steroid consumption: NA DMARD consumption: NA 299

312 Table C.3. Evidence table of clinical effect of omega-3 fatty acids in rheumatoid arthritis (continued). First Author, Year Study Characteristics Study Design Duration Eligibility Criteria Concurrent Disease Condition Medication Nielsen G, Sample size: 57 Age (mean/range): NA / Race: NA % male: NA Design: RCT Duration: 3.0 mo Inclusion: Covariates: Increased sed rate/>= 6 tender NSAIDs/DMARDs joints/>= 3 swollen joints/increased morning stiffness Exclusion: No current change in meds Arm Interventions Dosage/Duration 1 Control capsules (n-6 fatty acids) 6/day X 12 weeks 2 Pikasol (fish oil) capsules 6/d X 12 weeks # sites: 3 Location: Denmark 300

313 Table C.3. Evidence table of clinical effect of omega-3 fatty acids in rheumatoid arthritis (continued). First Author, Outcomes Year Results Nielsen G, Pain (Visual pain score at week 12) Arm 1 =136 Arm 2 =104 effect size=-0.85 (-1.42, -0.27) Reported testing: Article reports significant differences (p=0.002) between Arm 1 and Arm 2. Swollen joints (0-2 three point index scale at wee 12) Arm 1 =8 Arm 2 =8 effect size=0.00 (-0.55, 0.55) Reported testing: Article did not report statistical results comparing Arm 1 and Arm 2. Quality Applicability Funding Source Quality: Jadad: 4 Concealment of allocation: NR Applicability: NR Comments: Meta-analysis performed on patient assessment of pain, acute phase reactant, and swollen joints. Funding source: Private, non-industry Acute phase reactant (mm/hour at week 12) Arm 1 =33 Arm 2 =34 effect size=0.06 (-0.49, 0.61) Reported testing: Article did not report statistical results comparing Arm 1 and Arm 2. Patient global assessment: NA Radiographic damage: NA NSAID consumption: (at week 12) Arms 1, 2 = point estimate not reported Meta-analysis: Not performed, too few studies to pool. Reported testing: No difference within group, testing between groups not reported. Steroid consumption: (at week 12) Arms 1, 2 = point estimate not reported Meta-analysis: Not performed, too few studies to pool. Reported testing: No difference within group, testing between groups not reported. DMARD consumption(at week 12) Arms 1, 2 = point estimate not reported Meta-analysis: Not performed, too few studies to pool. Reported testing: No difference within group, testing between groups not reported. 301

314 Table C.3. Evidence table of clinical effect of omega-3 fatty acids in rheumatoid arthritis (continued). First Author, Year Study Characteristics Study Design Duration Eligibility Criteria Concurrent Disease Condition Medication Arm Interventions Dosage/Duration Nordstrom D, Sample size: Age (mean/range): 52 / Race: NA Design: RCT Duration: 3 mo Inclusion: NA Exclusion: NA Covariates: NSAIDs/DMARDs 1 Safflower oil 30 g/day X 3 mo 2 Flaxseed oil 30 g/day X 3 mo % male: NA # sites: 1 Location: Finland 302

315 Table C.3. Evidence table of clinical effect of omega-3 fatty acids in rheumatoid arthritis (continued). First Author, Outcomes Year Results Nordstrom D, Pain (Visual analogue scale at month 3) Arm 1 =4.60 Arm 2 =4.00 effect size=-0.21 (-1.04, 0.63) Reported testing: Article did not report statistical results comparing Arm 1 and Arm 2. Swollen Joints (Kaarela sjoint score index at month 3) Arm 1 =9.50 Arm 2 =9.10 effect size=-0.06 (-0.90, 0.77) Reported testing: Article did not report statistical results comparing Arm 1 and Arm 2. Quality Applicability Funding Source Quality: Jadad: 3 Concealment of allocation: NR Applicability: NR Funding source: Government; Private, non-industry Acute phase reactant (mm/hour at month 3) Arm 1 =32.50 Arm 2 =35.70 effect size=0.13 (-0.71, 0.96) Reported testing: Article did not report statistical results comparing Arm 1 and Arm 2. Patient global assessment (five-scale at month 3) Arm 1 =2.70 Arm 2 =2.90 effect size=0.26 (-0.58, 1.10) Reported testing: Article did not report statistical results comparing Arm 1 and Arm 2. Radiographic damage: NA NSAID consumption: NA Steroid consumption: NA DMARD consumption: NA 303

316 Table C.3. Evidence table of clinical effect of omega-3 fatty acids in rheumatoid arthritis (continued). First Author, Year Study Characteristics Study Design Duration Eligibility Criteria Concurrent Disease Condition Medication Skoldstam L, Sample size: Age (mean/range): 57 / Race: NA % male: 26 # sites: NA Design: RCT Duration: 6 mo Inclusion: Clinically stable/stable medication/increased sed rate/increased morning stiffness/>= 6 tender joints/>= 3 swollen joints Exclusion: NA Covariates: NSAIDs/DMARDs Arm Interventions Dosage/Duration 1 Control oil (maize, olive and peppermint oil) capsules 10 g/day X 6 mo 2 Max EPA (fish oil) 10 g/day X 6 mo Location: Sweden 304

317 Table C.3. Evidence table of clinical effect of omega-3 fatty acids in rheumatoid arthritis (continued). First Author, Outcomes Year Results Skoldstam L, Pain (0-3 VAS at month 3) Arm 1 mean=1.28 Arm 2 mean=136 effect size=0.11 (-0.49, 0.71) Reported testing: Article did not report statistical results comparing Arm 1 and Arm 2. Swollen joints: NA Quality Applicability Funding Source Quality: Jadad: 3 Concealment of allocation: NR Applicability: IB Funding source: Government Acute phase reactant (mm/hour at month 3) Arm 1 =39 Arm 2 =40 effect size=0.04 (-0.55, 0.64) Reported testing: Article did not report statistical results comparing Arm 1 and Arm 2. Patient global assessment (0-3 scale at month 3) Arm 1 =1.11 Arm 2 =1.20 effect size=0.04 (-0.56, 0.63) Reported testing: Article did not report statistical results comparing Arm 1 and Arm 2. Radiographic damage: NA NSAID consumption: NA Steroid consumption: NA DMARD consumption: NA 305

318 Table C.3. Evidence table of clinical effect of omega-3 fatty acids in rheumatoid arthritis (continued). First Author, Year Study Characteristics Study Design Duration Eligibility Criteria Concurrent Disease Condition Medication Arm Interventions Dosage/Duration Tulleken J, Sample size: 28 Age (mean/range): 55 / Race: NA Design: RCT Duration: 3 mo Inclusion: Stable medication Exclusion: NA Covariates: NSAIDs/DMARDs 1 Coconut oil capsules 4 TID X 3 mo 2 Fish oil capsules 4 TID (6 g/day) X 3 mo % male: 11 # sites: NA Location: Italy 306

319 Table C.3. Evidence table of clinical effect of omega-3 fatty acids in rheumatoid arthritis (continued). First Author, Outcomes Year Results Tulleken J, Pain (10 cm VAS at month 3) Arm 1 =3.8 Arm 2 =2.4 effect size=-0.72 (-1.50, 0.06) Reported testing: Article reports no significant differences (p>0.05) between Arm 1 and Arm 2. Swollen joints ((# of swollen joint at month 3) Arm 1 =4 Arm 2 =3 effect size=-0.26(-1.02, 0.50) Reported testing: Article reports no significant differences (p>0.05) between Arm 1 and Arm 2. Acute phase reactant (mm/hour at month 3) Arm 1 =53 Arm 2 =21 effect size=-1.82 (-2.71, -0.92) Reported testing: Article reports no significant differences (p>0.05) between Arm 1 and Arm 2. Quality Applicability Funding Source Quality: Jadad: 4 Concealment of allocation: Yes Applicability: IIB Comments: Meta-analysis performed on patient assessment of pain, swollen joints, and acute phase reactant. Funding source: Private, nonindustry Patient global assessment: NA Radiographic damage: NA NSAID consumption: NA Steroid consumption: NA DMARD consumption: NA 307

320 Table C.3. Evidence table of clinical effect of omega-3 fatty acids in rheumatoid arthritis (continued). First Author, Year Study Characteristics Study Design Duration Eligibility Criteria Concurrent Disease Condition Medication Arm Interventions Dosage Duration Tulleken J, Sample size: NA Age (mean/range): NA / NA Race: NA % male: NA # sites: NA Design: RXT Duration: 24 X-over: week 13 Run-in: NR Wash-out: NR Inclusion: Active RA Exclusion: NR Covariates: NSAIDs/DMARDs 1 Coconut oil capsules 12/day X 3 mo 2 Fish oil capsules 12/day X 3 mo Location: Netherlands 308

321 Table C.3. Evidence table of clinical effect of omega-3 fatty acids in rheumatoid arthritis (continued). First Author, Outcomes Year Results Quality Applicability Funding Source Tulleken J, Pain: NA Swollen joints: (at month 3) Arms 1, 2 = point estimates not reported Meta-analysis: Not included; point estimates not reported. Reported testing: Significant difference between arms favoring fish oil, test not stated. Acute phase reactant: (CRP, mg/dl, at month 3) Arms 1, 2 = point estimates not reported before cross-over Meta-analysis: Not included; point estimates not reported. Reported testing: No significant difference between arms, test not stated. Patient global assessment: NA Radiographic damage: NA NSAID consumption: NA Steroid consumption: NA DMARD consumption: NA Quality: Jadad: 2 Concealment of allocation: NR Applicability: NR Funding source: ND 309

322 Table C.3. Evidence table of clinical effect of omega-3 fatty acids in rheumatoid arthritis (continued). First Author, Year Study Characteristics Study Design Duration Eligibility Criteria Concurrent Disease Condition Medication Arm Interventions Dosage Duration van der Tempel H, Sample size: NA Age (mean/range): 53 / NA Race: NA % male: 44 # sites: NA Design: RXT Duration: 36 wk X-over: week 13 Run-in: 12 wk Wash-out: None Inclusion: NR Exclusion: NR Covariates: NSAIDs/DMARDs 1 Coconut oil capsules 12/day X 12 wk 2 Fish oil capsules 12/day X 12 wk Location: Netherlands 310

323 Table C.3. Evidence table of clinical effect of omega-3 fatty acids in rheumatoid arthritis. First Author, Outcomes Year Results van der Tempel H, Pain:(VAS, cm at week 12) Arms 1, 2 = point estimates not reported. Meta-analysis: Not included; point estimates not reported before cross-over. Reported testing: No significant differences between arms using t-test. Swollen joints: (at week 12) Arms 1, 2 = point estimates not reported. Meta-analysis: Not included; point estimates not reported before cross-over. Reported testing: Significant differences between favoring fish oil using t-test. Acute phase reactant: (CRP, mg/dl, at month 3) Arms 1, 2 = point estimates not reported before cross-over Meta-analysis: Not included; point estimates not reported. Reported testing: No significant differences between arms using t-test. Quality Applicability Funding Source Quality: Jadad: 4 Concealment of allocation: NR Applicability: IB Comments: Meta-analysis not performed because data was not reported by arm separately. Funding source: Private, non-industry Patient global assessment: NA Radiographic damage: NA NSAID consumption: NA Steroid consumption: NA DMARD consumption: NA 311

324 Table C.3. Evidence table of clinical effect of omega-3 fatty acids in rheumatoid arthritis (continued). First Author, Year Study Characteristics Study Design Duration Eligibility Criteria Concurrent Disease Condition Medication Volker D, Sample size: 50 Age (mean/range): 57 / NA Design: RCT Duration: 15 wk Inclusion: Stable medication/active disease/diet<10g n-6 fatty acids Covariates: NSAIDs/DMARDs Arm Interventions Dosage/Duration 1 Corn (50%)/olive oil (50%) soft gel capsules 40 mg/kg body weight/day x 15 wk Race: NA % male: NA # sites: NA Location: Australia Exclusion: NA 2 Pikasol (fish oil) capsules 40 mg/kg body weight/day x15 wk 312

325 Table C.3. Evidence table of clinical effect of omega-3 fatty acids in rheumatoid arthritis (continued). First Author, Outcomes Year Results Volker D, Pain: (percent change at week 15) Arm 1 = -8.6 Arm 2 = Meta-analysis: Not included; data reported as percent change. Reported testing: No significant differnce between goups by MANOVA. Swollen joints: (percent change at week 15) Arm 1 = Arm 2 = Meta-analysis: Not included; data reported as percent change. Reported testing: No significant differnce between goups by MANOVA. Quality Applicability Funding Source Quality: Jadad: 3 Concealment of allocation: NR Applicability: NR Funding source: Industry, private nonindustry Acute phase reactant: (ESR, percent change at week 15) Arm 1 = Arm 2 = -6.2 Meta-analysis: Not included; data reported as percent change. Reported testing: No significant differnce between goups by MANOVA. Patient global assessment: NA Radiographic damage: NA NSAID consumption: NA Steroid consumption: NA DMARD consumption: NA 313

326 Table C.4. Evidence table of clinical effect of omega-3 fatty acids in renal disease. First Author, Study Characteristics Study Design Year Duration Eligibility Criteria Covariates Arm Bennett WM, Sample size: Age (mean/range) Race 39 / NA NA % male : 57 # sites: NA Design: RCT Duration: 24 mo Inclusion Biopsy-proven Ig A nephropathy Exclusion: Baseline serum creatinine>0.40 mmol/l or = 0.12 mmol/l without active disease Covariates: Renal/Proteinuria/ Nephrotic Renal impairment: scr > 0.12 mm/l Interventions Dosage/Duration 1 No treatment x 24 mo 2 Max EPA (fish oil) 10 g/d x 24 mo Location: Australia 314

327 Table C.4. Evidence table of clinical effect of omega-3 fatty acids in renal disease (continued). First Author, Outcomes Year Results Bennett WM, Serum creatinine (change mmol/l at month 24): Arm 1= Subjects with baseline > 0.12 mmol/l = 0.22; Subjects with baseline <0.12 mmol/l, but with active disease = 0.01 Arm 2 = Subjects with baseline >0.12 mmol/l = 0.19; Subjects with baseline <0.12 mmol/l, but with active disease = 0.07 ±.06 Meta-anlysis: Not done; too few studies to pool. Reported testing: Testing between arms not reported. Creatinine clearance (change ml/min at month 24): Arm 1= -21 Arm 2 = -23 Meta-anlysis: Not done; too few studies to pool. Reported testing: Testing between arms not reported. ESRD (rate at month 24): Arm 1= 10% Arm 2 = 12% Meta-anlysis: Not done; too few studies to pool. Reported testing: Testing between arms not reported. Graft thrombosis: NA Mortality: NA Immunosuppressive requirement: NA Quality Applicability Funding Source Quality: Jadad: 2 Concealment of allocation: NA Applicability: IIB Funding source: NA 315

328 Table C.4. Evidence table of clinical effect of omega-3 fatty acids in renal disease (continued). Study Characteristics First Author, Study Design Year Duration Eligibility Criteria Covariates Arm Clark WFP, Sample size: Age (mean/range) 39 / Race: NA Design: RXT Duration: 13 mo X-over: month 5 Run-in: None Wash-out: 3 mo Inclusion: Lupus nephritis Exclusion: NA Covariates: NSAIDs/DMARDs Interventions Dosage/Duration 1 Olive oil 15 cap/d x 12 mo % male: 19 # sites: NA 2 Max EPA (fish oil) 15 cap/d x 12 mo Location: Canada De Fijter CW, Sample size: NA Design: RXT Duration: 27 mo Age (mean/range) NA / NA X-over: month 12 Run-in: None Race: NA Wash-out: 3 mo Inclusion: Dialysis/Start of erythropoietin/ Exclusion: NA Covariates: Hypertension 1 Corn oil 3 g/d x 5 mo % male: NA # sites: NA 2 EPA-B (fish oil) 3 g/d x 5 mo Location: Netherlands 316

329 Table C.4. Evidence table of clinical effect of omega-3 fatty acids in renal disease (continued). First Author, Outcomes Year Results Clark WFP, Serum creatinine (µmol/l at month 12): Arm 1= point estimate before cross-over not reported Arm 2 = point estimate before cross-over not reported Meta-analysis: Not done; too few studies to pool. Reported testing: No significant (p = 0.60) effect for fish oil (Arm 2) relative to olive oil (Arm 1). Creatinine clearance (ml/min/1.73 m 2 at at month 12): Arm 1= 78 Arm 2 = 75 Meta-anlysis: Not done; too few studies to pool. Reported testing: No significant difference between groups. Quality Applicability Funding Source Quality: Jadad: 3 Concealment of allocation: NA Applicability: IIIB Funding source: Private, non industry De Fijter CW, ESRD: NA Graft thrombosis: NA Mortality: NA Immunosuppressive requirement: NA Serum creatinine: NA Creatinine clearance: NA ESRD: NA Graft thrombosis (rate at month 5): Arm 1= 0% Arm 2 = 0% Meta-analysis: Not done; too few studies to pool. Reported testing: Testing between arms not reported. Mortality: NA Immunosuppressive requirement: NA Quality: Jadad: 3 Concealment of allocation: NA Applicability: NA Funding source: NA 317

330 Table C.4. Evidence table of clinical effect of omega-3 fatty acids in renal disease (continued). Study Characteristics Study Design Eligibility Criteria Covariates Arm First Author, Duration Year Donadio JV, Sample size: Age (mean/range): Race: 37 / NA Caucasian % male: 74 # sites: 21 Location: US Design: RCT Duration: 60 mo Inclusion: Biopsy-proven Ig A nephropathy /Proteinuria/Serum creatinine increased by 25%/Creatinine <3.0 mg/dl/expected survival of 2 or more years Exclusion: SLE/ Chronic liver disease/pregnancy/lactating/ Antiglomerular basement membrane glomerulonephritis Covariates: Renal/Proteinuria/Ne phrotic Interventions Dosage/Duration 1 Olive oil 12 g/d x 24 mo 2 Max EPA (fish oil) 12 g/d x 12 mo Menhaden oil (fish oil) 12 g/d x 12 mo 318

331 Table C.4. Evidence table of clinical effect of omega-3 fatty acids in renal disease (continued). First Author, Outcomes Year Results Donadio JV, Serum creatinine (Annual median change mg/dl at month 24): Arm 1= 0.14 Arm 2 = 0.03 Meta-anlysis: Not done; too few studies to pool. Reported testing: Significant (P = 0.001) effect for fish oil (Arm 2) relative to olive oil (Arm 1) using rank-sum test. Creatinine clearance(annual median change ml/min/1.73 m 2 at at month 24): Arm 1= -7.1 Arm 2 = -0.3 Meta-anlysis: Not done; too few studies to pool. Reported testing: Significant (P = 0.009) effect for fish oil (Arm 2) relative to olive oil (Arm 1) using rank-sum test. Quality Applicability Funding Source Quality: Jadad: 4 Concealment of allocation: NR Applicability: IIB Funding source: Hospital and Industry ESRD (rate at month 60): Arm 1= 28% Arm 2 = 7% Meta-anlysis: Not done; too few studies to pool. Reported testing: Significant effect for fish oil (Arm 2) relative to olive oil (Arm 1) using rank-sum test and Kaplan-Meier analysis. Graft thrombosis: NA Mortality(rate at month 60): Arm 1= 1% Arm 2 = 2% Meta-anlysis: Meta-analysis not performed on renal studies due to insufficient statistics. Reported testing: No significant effect for fish oil (Arm 2) relative to olive oil (Arm 1) using rank-sum test and Kaplan-Meier analysis. Immunosuppressive requirement: NA 319

332 Sample size: 73 Table C.4. Evidence table of clinical effect of omega-3 fatty acids in renal disease (continued). First Author, Year Study Characteristics Study Design Duration Eligibility Criteria Covariates Arm Interventions Dosage/Duration Donadio JV, Design: RCT 1 Omacor g/d x 24 mo Age (mean/range): Race: 46 / NA Caucasian % male: 83 # sites: 14 Duration: 60 mo Inclusion: Biopsy-proven Ig A nephropathy /Age/Serum creatinine mg/dl Exclusion: NA Covariates: Previous meds tx/ Hypertension 2 Omacor 8 g/d x 24 mo Location: US 320

333 Table C.4. Evidence table of clinical effect of omega-3 fatty acids in renal disease (continued). First Author, Outcomes Year Results Donadio JV, Serum creatinine (annual median change, mg/dl at month 60): Arm 1= 0.08 Arm 2 = 0.10 Meta-anlysis: Not done; too few studies to pool. Reported testing: No significant (P = 0.51) effect for high dose Omacor (Arm 2) relative to low dose Omacor(Arm 1) using rank-sum test. Creatinine clearance: NA Quality Applicability Funding Source Quality: Jadad: 2 Concealment of allocation: NA Applicability: IIB Funding source: Hospital and Industry ESRD ((rate at month 36): Arm 1= 27% Arm 2 = 24% Meta-anlysis: Not done; too few studies to pool. Reported testing: No significant (P = 0.56) effect for high dose Omacor (Arm 2) relative to low dose Omacor(Arm 1) using rank-sum test. Graft thrombosis: NA Mortality (rate at month 36): Arm 1= 0% Arm 2 = 0% Meta-anlysis: Not done; too few studies to pool. Reported testing: No significant effect for high dose Omacor (Arm 2) relative to low dose Omacor(Arm 1) using rank-sum test. Immunosuppressive requirement: NA 321

334 Table C.4. Evidence table of clinical effect of omega-3 fatty acids in renal disease (continued). First Author, Year Study Characteristics Study Design Duration Eligibility Criteria Covariates Arm Interventions Dosage/Duration Gentile MG, Sample size: NA Age (mean/range): 45 / Race: NA % male: 45 # sites: 1 Design: RXT Duration: 9 mo X-over: month 4 Run-in: 2 mo Wash-out: None Inclusion: Biopsy-proven glomerular disease/proteinuria/ Hyperlipidemia Exclusion: Steroid treatment/cytotoxic treatment/nsaid treatment/lipid lowering drug treatment Covariates: soy diet 1 Soy diet alone Dosage NA x 2 mo 2 Soy diet Dosage NA x 2 mo Fish oil 5 g/d x 2 mo Location: Italy 322

335 Table C.4. Evidence table of clinical effect of omega-3 fatty acids in renal disease (continued). First Author, Outcomes Year Results Gentile MG, Serum creatinine (mg/dl at month 2): Arm 1= point estimate before cross-over not reported Arm 2 = point estimate before cross-over not reported Meta-anlysis: Not done; too few studies to pool. Reported testing: Testing between arms not reported. Creatinine clearance(ml/min atb month 2): Arm 1= point estimate before cross-over not reported Arm 2 = point estimate before cross-over not reported Meta-anlysis: Not done; too few studies to pool. Reported testing: Testing between arms not reported. Quality Applicability Funding Source Quality: Jadad: 2 Concealment of allocation: NA Applicability: IB Funding source: Government ESRD: NA Graft thrombosis: NA Mortality: NA Immunosuppressive requirement: NA 323

336 Table C.4. Evidence table of clinical effect of omega-3 fatty acids in renal disease (continued). First Author Year Study Characteristics Study Design Duration Eligibility Criteria Covariates Arm Interventions Dosage/Duration Pettersson EE, Sample size: Age (mean/range): 41 / Race: NA % male: 78 # sites: NA Location: Sweden Design: RCT Duration: 6 mo Inclusion : Biopsy-proven Ig A nephropathy /Proteinuria Exclusion: SLE/Steroid treatment /Cytotoxic or immunosuppressive drug treatment/nsaid treatment /Diabetes/Malignant disease/heart failure/rapidly progressive renal insufficiency/uncontrolled hypertension Covariates: Proteinuria/ nephrotic 1 Corn oil 6g/d x 6 mo 2 K-85 (fish oil) 6g/d x 6 mo 324

337 Table C.4. Evidence table of clinical effect of omega-3 fatty acids in renal disease (continued). First Author, Outcomes Year Results Pettersson EE, Serum creatinine(change µmol/l at month 6): Arm 1= 1 Arm 2 = 8 Meta-anlysis: Not done; too few studies to pool. Reported testing: Testing between arms not reported. Quality Applicability) Funding Source Quality: Jadad: 4 Concealment of allocation: NA Applicability: IIB Funding source: NA Creatinine clearance (change ml/min at month 6): Arm 1= 0 Arm 2 = 12 Meta-anlysis: Not done; too few studies to pool. Reported testing: Testing between arms not reported. ESRD: NA Graft thrombosis: NA Mortality: NA Immunosuppressive requirement: NA 325

338 Table C.4. Evidence table of clinical effect of omega-3 fatty acids in renal disease (continued). First Author Year Study Characteristics Study Design Duration Eligibility Criteria Covariates Arm Interventions Dosage/Duration Schmitz PG, Sample size: Age (mean/range): Race: 53 / NA Black % male: 46 # sites: 1 Location: US Design: RCT Duration: 12 mo Inclusion: Initiation of hemodialysis with PTFE graft/hemodialysis with new placement of PTFE graft Exclusion: Pregnancy/lactating/Surgical revision of graft/history of GI bleeding/chronic anticoagulation treatment/ Malignant hypertension/terminal of lifethreatening diseases Covariates: Hyperlipidemia/ Hypertension/ Diabetes/Venous output resistance 1 Corn oil 4g/d x 12 mo 2 Fish oil 4g/d x 12 mo 326

339 Table C.4. Evidence table of clinical effect of omega-3 fatty acids in renal disease (continued). First Author, Outcomes Year Results Schmitz PG, Serum creatinine: NA Creatinine clearance: NA ESRD:NA Graft thrombosis(rate at 12 mo): Arm 1= 75% Arm 2 = 25% Meta-analysis: Not done; too few studies to pool. Reported testing: Testing between arms not reported. Quality Applicability Funding Source Quality: Jadad: 4 Concealment of allocation: NA Applicability: IIB Funding source: Private, non-industry and Government Patency (rate at 12 mo): Arm 1= 15% Arm 2 = 76% Meta-analysis: Not done; too few studies to pool. Reported testing: Significant (p <.03) effect for fish oil (Arm 2) relative to corn oil (Arm 1) using Mantel- Cox test. Mortality: NA Immunosuppressive requirement: NA 327

340 Table C.5. Evidence table of clinical effects of omega-3 fatty acids in systemic lupus erythematosus. First Author, Year Study Characteristics Study design Duration Eligibility Criteria Concurrent Disease Condition Medication Clark WF, Sample size: 26Design: RXT Age (mean/range): 39 / 22-66Duration: 24 mo Race: NAX-over: month 13 Inclusion: Lupus nephritis Exclusion: NA Covariates: NSAIDs/DMARDs Arm Interventions Dosage/Duration 1 Olive oil capsules 15/d x 12 mo 2 Max EPA (fish oil) 15/d x 12 mo % male: 19Run-in: None # sites: NAWash-out: 10 wk Location: Canada Walton AJ, Design: RXT Sample size: 27 Age (mean/range): NA / 21-68Duration: 34 wk Race: NA X-over: week 22 % male: 7Run-in: 2 wk # sites: 1Wash-out: 8 wk Inclusion: Established SLE Covariates: NA 1 Olive oil 20g/d x 12 wk 2 Max EPA (fish oil) 20g/d x 12 wk Location: UK 328

341 Table C.5. Evidence table of clinical effects of omega-3 fatty acids in systemic lupus erythematosus (continued). First Author, Outcomes Year Results Clark WF, Disease activity: (SLEDAI score at month 12) Arm 1= point estimate not reported Arm 2 = point estimate not reported Meta-analysis: Not done; too few studies to pool. Reported testing: No change in SLEDAI scores for either arm, statistical test used and comparison between arms for this outcome not explicitly stated. Disease activity: (anti-ds-dna Ab level at month 12) Arm 1= point estimate not reported Arm 2 = point estimate not reported Meta-analysis: Not done; too few studies to pool. Reported testing: No treatment (p=0.71), time (p=0.25), order (p=0.35) or carry-over effect (p=0.92); statistical test used not stated. Damage: NA Quality Applicability Funding Source Quality: Jadad: 3 Concealment of allocation: NA Applicability: IIIB Private, non- Funding source: industry Walton AJ, Patient perception: NA Disease Activity: (Unspecified individualized responses defined a priori and based on change in clinical and laboratory parameters at month 6) Arm 1: 4/17 useful/ideal status 13/17 static/worse status Arm 2: 14/17 useful/ideal status 3/17 static/worse status Meta-analysis: Not done; too few studies to pool. Reported testing: Testing between groups not reported. Damage: NA Patient perception: NA Quality: Jadad: 3 Concealment of allocation: Yes Applicability: IIB Funding source: non-industry government; private, 329

342 Table C.5. Evidence table of clinical effects of omega-3 fatty acids in systemic lupus erythematosus (continued). First Author, Year Study Characteristics Study design Duration Eligibility Criteria Concurrent Disease Condition Medication Sample size: 20 Westberg G, Design: RXT Age (mean/range): 44 / 31-64Duration: 21 mo Race: NAX-over: month 12 Inclusion: Stable medication Exclusion: Inactive disease Covariates: DMARDs, steroid use Arm Interventions Dosage/Duration 1 Placebo/control Dosage/duration not collected 2 Max EPA (fish oil) Variable dose for 6 mo % male: 12Run-in: 3 mo # sites: 2Wash-out: 3 mo Location: Australia 330

343 Table C.5. Evidence table of clinical effects of omega-3 fatty acids in systemic lupus erythematosus (continued). First Author, Outcomes Year Results Westberg G, Disease activity: (Author s own instrument, at 6 mo) Arm 1= point estimates not reported. Arm 2 = point estimates not reported. Meta-analysis: Not done; too few studies to pool. Reported testing: No significant difference between groups using Student s t-test. Disease activity: (anti-dna Ab level at month 6) Arm 1= point estimate not reported Arm 2 = point estimate not reported Meta-analysis: Not done; too few studies to pool. Reported testing No significant difference between groups using Student s t-test. Quality Applicability Funding Source Quality: Jadad: 5 Concealment of allocation Yes Applicability: IIB Funding source: NA Damage: NA Patient Perception: NA 331

344 Table C.6. Evidence table of clinical effect of omega-3 fatty acids in bone mineral density/osteoporosis. First Author, Study Characteristics Study Design Eligibility Criteria Concurrent Year Duration Disease Condition Medication Bassey EJ, Study A Sample size: 64 Age (mean/range): 35 / Race: NA % male: 0 # sites: 1 Design: Duration: RCT Inclusion: Age/Pre-menopausal 12 mo Exclusion: Health problems/bmi>36, <18/BMD outside 2SD of norms/confounding drug therapy/pregnancy/lactating/ Dietary supplements/irregular menses Arm Interventions Dosage/Duration Covariates: Weight/Age/Di 1 Calcium 1g/d x 12 mo etary Calcium 2 Efacal (Ca, Primrose oil, Fish oil) Ca 1 g/d x 12 mo Evening prim rose oil 4 g/d x 12 mo Fish oil 440 g/d x 12 mo Bassey EJ, Study B Location: UK Sample Size: 57Design: Age (mean/range): 57/50-65Duration: race: NA % male: 0 # sites: 1 RCT Inclusion: Age/Postmenopausal 12 mo Exclusion: Health problems/ BMI >36, <18/BMD outside 2SD of norms/confounding drug therapy/dietary supplements/ within 1 yr of menopause/hormone levels outside of normal postmenopausal range/hormone replacement therapy Covariates: Weight/Age/Di 1 Calcium 1g/d x 12 mo etary Calcium 2 Efacal (Ca, Primrose oil, Fish oil) Ca 1 g/d x 12 mo Evening primrose oil 4 g/d x 12 mo Fish oil 440 g/d x 12 mo Location: UK 332

345 Table C.6. Evidence table of clinical effect of omega-3 fatty acids in bone mineral density/osteoporosis (continued). First Author, Outcomes Year Results Bassey EJ, Study A Bone mineral density: (change at month 12, g/cm 2 ) Arm 1= Arm 2 = Meta-analysis: Not done; too few studies to pool. Reported testing: Significant (p<.001) difference between groups using paired Student s t-test. Quality Applicability Funding Source Quality: Jadad: 2 Concealment of allocation: Yes Applicability: IA Bassey EJ, Study B Fractures: NA Bone mineral density: (change at month 12, g/cm 2 ) Arm 1= Arm 2 = Meta-analysis: Not done; too few studies to pool. Reported testing: Significant (p<.001) difference between groups using paired Student s t-test. Funding source: Industry Quality: Jadad: 2 Concealment of allocation: Applicability: IA Yes Fractures: NA Funding source: Industry 333

346 Table C.6. Evidence table of clinical effect of omega-3 fatty acids in bone mineral density/osteoporosis (continued). First Author, Study Characteristics Study Design Eligibility Criteria Concurrent Year Duration Disease Condition Medication Kruger MC, Sample size: 66 starting Age (mean/range): Race: 80 / NA Duration: NA % male: 0 Design: RCT 18 mo Inclusion: Osteoporosis confirmation by BMD Exclusion: Metabolic bone disease/ Diabetes/Renal failure Covariates: Weight/Age Arm Interventions Dosage/Duration 1 Coconut oil 6 g/d X 18 mo 2 Fish oil 6 g/d X 18 mo 2 EPA 2g x 12 mo plus HMGCoA reductace inhibitor # sites: NA Location: South Africa 334

347 Table C.6. Evidence table of clinical effect of omega-3 fatty acids in bone mineral density/osteoporosis (continued). First Author, Year Outcomes Results Quality Applicability Funding Source Kruger MC, Bone mineral density: (lumbar spine, g/cm 2 at month 18) Arm 1= Arm 2 = Meta-analysis: Not done; too few studies to pool. Reported testing: Testing between groups not reported. Quality: Jadad: 2 Concealment of allocation: Applicability: IIIB NA Bone mineral density: (femoral neck, g/cm 2 at month 18) Arm 1= Arm 2 = Meta-analysis: Not done; too few studies to pool. Reported testing: Testing between groups not reported. Funding source: Industry Fractures: (cumulative number at month 18) Arm 1= 0 Arm 2 = 0 Meta-analysis: Not done; too few studies to pool. Reported testing: Testing between groups not reported. 335

348 Table C.6. Evidence table of clinical effect of omega-3 fatty acids in bone mineral density/osteoporosis (continued). First Author, Year Study Characteristics Study Design Duration Eligibility Criteria Concurrent Disease Condition Medication Terano T, Sample size: 33 Design: RCT Inclusion: Hyperlipidemia Covariates: Hyperlipidemia/Age/ Age (mean/range): 58 / NA Duration: 12 mo Exclusion: NA Weight Arm Interventions Dosage/Duration 1 HMGCoA reductase inhibitor Race: NA % male: 0 # sites: NA Location: Japan 336

349 Table C.6. Evidence table of clinical effect of omega-3 fatty acids in bone mineral density/osteoporosis (continued). First Author, Outcomes Year Results Terano T, Bone mineral density: (speed of sound, %, at month 12) Arm 1= 98.6 Arm 2 = 99.3 Meta-analysis: Not done; too few studies to pool. Reported testing: Testing between groups not reported. Quality Applicability Funding Source Quality: Jadad: 1 Concealment of allocation: NR Applicability: Not described Bone mineral density: (transmission index, %, at month 12) Arm 1= 99.4 Arm 2 = 101 Meta-analysis: Not done; too few studies to pool. Reported testing: Testing between groups not reported. Bone mineral density: (osteosono assessment index, %, at month 12) Arm 1= 99.4 Arm 2 = 99.3 Meta-analys is: Not done; too few studies to pool. Reported testing: Testing between groups not reported. Fractures: NA Funding source: NR 337

350 Table C.6. Evidence table of clinical effect of omega-3 fatty acids in bone mineral density/osteoporosis (continued). First Author, Year Study Characteristics Study Design Duration Eligibility Criteria Concurrent Disease Condition Medication Tsuchida K, Sample size: 995 Age (mean/range): 45 / Race: Asian % male: 0 # sites: 18 Location: Japan Design: Duration: Cohort NA Inclusion: Age Exclusion: Medical treatment/ovalectomy Covariates: Weight/Age/Dietary Calcium/Menstrual cycle Arm Interventions Dosage/Duration 1 Fish -0-1 portions/week 2 Fish 2-5 portions/week 3 Fish 6-7 portions/week 4 Soybean 0-1 portions/week 5 Soybean 2-5 portions/week 6 Soybean 6-7 portions/week 338

351 Table C.6. Evidence table of clinical effect of omega-3 fatty acids in bone mineral density/osteoporosis (continued). First Author, Outcomes Year Results Tsuchida K, Bone mineral density: There was no association between fish intake and BMD of the 2 nd metacarpal bone. Soybean intake was associated with a significant (p=.03 by ANOVA) gradient in BMD of 2 nd metacarpal independent of age, height, weight and weekly calcium intake. Those with 2 or more portions were significantly higher than 0-1 portions. Fractures: NA Quality Applicability Funding Source Quality Jadad: NA Concealment of allocation: NA Applicability: IA Funding source: NR 339